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Chávez-Castillo, Mervin, Ángel Ortega, Lorena Cudris-Torres, Pablo Duran, Milagros Rojas, Alexander Manzano, Bermary Garrido, et al. "Specialized Pro-Resolving Lipid Mediators: The Future of Chronic Pain Therapy?" International Journal of Molecular Sciences 22, no. 19 (September 26, 2021): 10370. http://dx.doi.org/10.3390/ijms221910370.
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Chronic pain (CP) is a severe clinical entity with devastating physical and emotional consequences for patients, which can occur in a myriad of diseases. Often, conventional treatment approaches appear to be insufficient for its management. Moreover, considering the adverse effects of traditional analgesic treatments, specialized pro-resolving lipid mediators (SPMs) have emerged as a promising alternative for CP. These include various bioactive molecules such as resolvins, maresins, and protectins, derived from ω-3 polyunsaturated fatty acids (PUFAs); and lipoxins, produced from ω-6 PUFAs. Indeed, SPMs have been demonstrated to play a central role in the regulation and resolution of the inflammation associated with CP. Furthermore, these molecules can modulate neuroinflammation and thus inhibit central and peripheral sensitizations, as well as long-term potentiation, via immunomodulation and regulation of nociceptor activity and neuronal pathways. In this context, preclinical and clinical studies have evidenced that the use of SPMs is beneficial in CP-related disorders, including rheumatic diseases, migraine, neuropathies, and others. This review integrates current preclinical and clinical knowledge on the role of SPMs as a potential therapeutic tool for the management of patients with CP.
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Perniola, S., S. Alivernini, B. Tolusso, M. R. Gigante, M. Gessi, C. Di Mario, L. Petricca, et al. "AB0102 SPECIALIZED PRO-RESOLVING MEDIATOR RECEPTORS AS INFLAMMATORY RESOLUTION BIOMARKERS IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1350.3–1350. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6303.
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Background:The regulation of inflammation is a dynamic process involving several molecules as lipid mediators. The Specialized Pro-resolving Mediators (SPMs), such as Resolvin (RvD and RvE), Protectins, Maresins and Lipoxin A4 (LXA4), are bioactive metabolites of omega-3 and omega-6 fatty acids which drive inflammatory resolution phase and promote tissue repair. ERV, ALX/FPR2 and BLT1 are SPM receptors. Although in Rheumatoid Arthritis (RA) lipid mediators role within pathophysiology is under definition, studies on SPMs receptors role are still lacking in this disease.Objectives:Purpose of this study is to define ERV, ALX/FPR2 and BLT1 expression in blood derived leukocytes and synovial cells and to correlate it to disease activity to define SPM receptors ad inflammatory resolution biomarkers in RA patients.Methods:A cohort of 52 RA patients was enrolled in the study of which 40 with active disease (DAS28= 5,35 (5,18-6,40)) and 12 in sustained remission status (DAS28= 2,1 (1,83-2,42)). Each enrolled patient underwent peripheral blood (PB) drawing and 46 of them underwent US-guided synovial tissue (ST) biopsy. FACS gating strategy was used for PB and ST processing to evaluate percentage of positive cells and the mean fluorescence intensity (MFI) of ERV+, ALX/FPR2+and BLT1+in CD45+CD3+, CD45+CD19+for PB and ST, CD45+CD14+and neutrophils for PB only and CD45-CD90+, CD45+CD64+CD11b+macrophages (distinct in CD206+and CD206-subpopulations) for ST only. Each included ST was stained with haematoxylin/eosin and categorized by a pathologist, blinded to clinical characteristics, using the Krenn Score (KS) to assess ST inflammation degree. As control group, 11 undifferentiated peripheral inflammatory arthritis (UPIA) patients were enrolled in the study.Results:Considering the whole RA cohort, DAS28 inversely correlated with BLT1+positive cells on ST-derived CD45+(r= -0.48; p= 0.048), CD3+(r= -0.56; p= 0.019) and CD19+(r= -0.49; p= 0.042) cells, in contrast with CD90+(r= 0.50; p= 0.041) cells. Similarly, both DAS28 and KS inversely correlated with ALX/FPR2+positive cells in ST-derived CD45+(r= -0.42, p= 0.050 and r= -0,41, p= 0,046 respectively) cells. Evaluating the MFI levels of the SPM receptors along all RA stages (naïve-to-treatment, resistant-to-treatment, sustained remission) compared with UPIA control group, interestingly ST-derived CD45+cells of remission RA were depleted of ERV1 compared to naïve-to-treatment RA (p=0.04), despite comparable ST inflammation. Furthermore, highest ERV1 expression was found in ST-derived CD45+CD3+and CD45+CD19+cells in naïve-to-treatment RA compared with UPIA patients (p= 0,045 and p= 0,012 respectively). Moreover, the lowest BLT1 level was found in remission RA CD3+cells compared with UPIA and naïve-to-treatment RA patients (p= 0,008 and p= 0,023 respectively).Conclusion:SPM receptors expression seem to be tightly related to disease activity in the synovial tissue, suggesting an important involvement in the inflammatory process in RA patient.References:[1]Serhan CN. Nature, 2014.[2]Alivernini S, et al. Arthritis Res Ther 2016[3]Krenn V et al. Histopathology, 2006.Disclosure of Interests:Simone Perniola: None declared, Stefano Alivernini: None declared, Barbara Tolusso: None declared, Maria Rita Gigante: None declared, Marco Gessi: None declared, Clara Di Mario: None declared, Luca Petricca: None declared, Annunziata Capacci: None declared, Anna Laura Fedele: None declared, Gianfranco Ferraccioli: None declared, Elisa Gremese Speakers bureau: Abbvie, BMS, Celgene, Jannsen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB
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Hwang, Sung-Min, Gehoon Chung, Yong Ho Kim, and Chul-Kyu Park. "The Role of Maresins in Inflammatory Pain: Function of Macrophages in Wound Regeneration." International Journal of Molecular Sciences 20, no. 23 (November 21, 2019): 5849. http://dx.doi.org/10.3390/ijms20235849.
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Although acute inflammatory responses are host-protective and generally self-limited, unresolved and delayed resolution of acute inflammation can lead to further tissue damage and chronic inflammation. The mechanism of pain induction under inflammatory conditions has been studied extensively; however, the mechanism of pain resolution is not fully understood. The resolution of inflammation is a biosynthetically active process, involving specialized pro-resolving mediators (SPMs). In particular, maresins (MaRs) are synthesized from docosahexaenoic acid (DHA) by macrophages and have anti-inflammatory and pro-resolving capacities as well as tissue regenerating and pain-relieving properties. A new class of macrophage-derived molecules—MaR conjugates in tissue regeneration (MCTRs)—has been reported to regulate phagocytosis and the repair and regeneration of damaged tissue. Macrophages not only participate in the biosynthesis of SPMs, but also play an important role in phagocytosis. They exhibit different phenotypes categorized as proinflammatory M1-like phenotypes and anti-inflammatory M2 phenotypes that mediate both harmful and protective functions, respectively. However, the signaling mechanisms underlying macrophage functions and phenotypic changes have not yet been fully established. Recent studies report that MaRs help resolve inflammatory pain by enhancing macrophage phagocytosis and shifting cytokine release to the anti-inflammatory M2 phenotypes. Consequently, this review elucidated the characteristics of MaRs and macrophages, focusing on the potent action of MaRs to enhance the M2 macrophage phenotype profiles that possess the ability to alleviate inflammatory pain.
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Tylek, Kinga, Ewa Trojan, Magdalena Regulska, Enza Lacivita, Marcello Leopoldo, and Agnieszka Basta-Kaim. "Formyl peptide receptor 2, as an important target for ligands triggering the inflammatory response regulation: a link to brain pathology." Pharmacological Reports 73, no. 4 (June 8, 2021): 1004–19. http://dx.doi.org/10.1007/s43440-021-00271-x.
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AbstractFormyl peptide receptors (FPRs) belong to the family of seven-transmembrane G protein-coupled receptors. Among them, FPR2 is a low affinity receptor for N-formyl peptides and is considered the most promiscuous member of FPRs. FPR2 is able to recognize a broad variety of endogenous or exogenous ligands, ranging from lipid to proteins and peptides, including non-formylated peptides. Due to this property FPR2 has the ability to modulate both pro- and anti-inflammatory response, depending on the nature of the bound agonist and on the different recognition sites of the receptor. Thus, FPR2 takes part not only in the proinflammatory response but also in the resolution of inflammation (RoI) processes. Recent data have indicated that the malfunction of RoI may be the background for some central nervous system (CNS) disorders. Therefore, much interest is focused on endogenous molecules called specialized pro-resolving mediators (SPMs), as well as on new synthetic FPR2 agonists, which kick-start the resolution of inflammation (RoI) and modulate its course. Here, we shed some light on the general characteristics of the FPR family in humans and in the experimental animals. Moreover, we present a guide to understanding the “double faced” action of FPR2 activation in the context of immune-related diseases of the CNS.
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Trojan, Ewa, Natalia Bryniarska, Monika Leśkiewicz, Magdalena Regulska, Katarzyna Chamera, Magdalena Szuster-Głuszczak, Marcello Leopoldo, Enza Lacivita, and Agnieszka Basta-Kaim. "The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology." Current Neuropharmacology 18, no. 3 (February 14, 2020): 229–49. http://dx.doi.org/10.2174/1570159x17666191019170244.
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: Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. : This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.
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Vassallo, Arlette, Alex J. Wood, Julien Subburayalu, Charlotte Summers, and Edwin R. Chilvers. "The counter-intuitive role of the neutrophil in the acute respiratory distress syndrome." British Medical Bulletin 131, no. 1 (September 2019): 43–55. http://dx.doi.org/10.1093/bmb/ldz024.
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Abstract Introduction Neutrophils are the primary effectors of the innate immune system but are profoundly histotoxic cells. The acute respiratory distress syndrome (ARDS) is considered to be a prime example of neutrophil-mediated tissue injury. Sources of data The information presented in this review is acquired from the published neutrophil cell biology literature and the longstanding interest of the senior authors in ARDS pathogenesis and clinical management. Areas of agreement Investigators in the field would agree that neutrophils accumulate in high abundance in the pulmonary microcirculation, lung interstitium and alveolar airspace of patients with ARDS. ARDS is also associated with systemic neutrophil priming and delayed neutrophil apoptosis and clearance of neutrophils from the lungs. In animal models, reducing circulating neutrophil numbers ameliorates lung injury. Areas of controversy Areas of uncertainty include how neutrophils get stuck in the narrow pulmonary capillary network—whether this reflects changes in the mechanical properties of primed neutrophils alone or additional cell adhesion molecules, the role of neutrophil sub-sets or polarization states including pro-angiogenic and low-density neutrophils, whether neutrophil extracellular trap (NET) formation is beneficial (through bacterial capture) or harmful and the potential for neutrophils to participate in inflammatory resolution. The latter may involve the generation of specialized pro-resolving molecules (SPMs) and MMP-9, which is required for adequate matrix processing. Growing points Different and possibly stable endotypes of ARDS are increasingly being recognized, yet the relative contribution of the neutrophil to these endotypes is uncertain. There is renewed and intense interest in understanding the complex ‘new biology’ of the neutrophil, specifically whether this cell might be a valid therapeutic target in ARDS and other neutrophil-driven diseases and developing understanding of ways to enhance the beneficial role of the neutrophil in the resolution phase of ARDS. Areas timely for developing research Aside from treatment of the precipitating causes of ARDS, and scrupulous fluid, infection and ventilation management, there are no pharmacological interventions for ARDS; this represents an urgent and unmet need. Therapies aimed at reducing overall neutrophil numbers risk secondary infection; hence better ways are needed to reverse the processes of neutrophil priming activation, hyper-secretion and delayed apoptosis while enhancing the pro-resolution functions of the neutrophil.
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Regidor, Pedro-Antonio, Anna Mueller, Manuela Sailer, Fernando Gonzalez Santos, Jose Miguel Rizo, and Fernando Moreno Egea. "Chronic Inflammation in PCOS: The Potential Benefits of Specialized Pro-Resolving Lipid Mediators (SPMs) in the Improvement of the Resolutive Response." International Journal of Molecular Sciences 22, no. 1 (December 31, 2020): 384. http://dx.doi.org/10.3390/ijms22010384.
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PCOS as the most common endocrine disorder of women in their reproductive age affects between 5–15% of the female population. Apart from its cardinal symptoms, like irregular and anovulatory cycles, hyperandrogenemia and a typical ultrasound feature of the ovary, obesity, and insulin resistance are often associated with the disease. Furthermore, PCOS represents a status of chronic inflammation with permanently elevated levels of inflammatory markers including IL-6 and IL-18, TNF-α, and CRP. Inflammation, as discovered only recently, consists of two processes occurring concomitantly: active initiation, involving “classical” mediators including prostaglandins and leukotrienes, and active resolution processes based on the action of so-called specialized pro-resolving mediators (SPMs). These novel lipid mediator molecules derive from the essential ω3-poly-unsaturated fatty acids (PUFAs) DHA and EPA and are synthesized via specific intermediates. The role and benefits of SPMs in chronic inflammatory diseases like obesity, atherosclerosis, and Diabetes mellitus has become a subject of intense research during the last years and since PCOS features several of these pathologies, this review aims at summarizing potential roles of SPMs in this disease and their putative use as novel therapeutics.
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Zaloga, Gary P. "Narrative Review of n-3 Polyunsaturated Fatty Acid Supplementation upon Immune Functions, Resolution Molecules and Lipid Peroxidation." Nutrients 13, no. 2 (February 18, 2021): 662. http://dx.doi.org/10.3390/nu13020662.
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Fish oil supplementation is commonplace in human nutrition and is being used in both enteral and parenteral formulations during the treatment of patients with a large variety of diseases and immune status. The biological effects of fish oil are believed to result from their content of n-3 polyunsaturated fatty acids (PUFA), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). These fatty acids are known to have numerous effects upon immune functions and are described as immunomodulatory. However, immunomodulatory is a nondescript term that encompasses immunostimulation and immunosuppression. The primary goal of this review is to better describe the immune effects of n-3 PUFA as they relate to immunostimulatory vs. immunosuppressive effects. One mechanism proposed for the immune effects of n-3 PUFA relates to the production of specialized pro-resolving mediators (SPMs). A second goal of this review is to evaluate the effects of n-3 PUFA supplementation upon production of SPMs. Although n-3 PUFA are stated to possess anti-oxidative properties, these molecules are highly oxidizable due to multiple double bonds and may increase oxidative stress. Thus, the third goal of this review is to evaluate the effects of n-3 PUFA upon lipid oxidation. We conclude, based upon current scientific evidence, that n-3 PUFA suppress inflammatory responses and most cellular immune responses such as chemotaxis, transmigration, antigen presentation, and lymphocyte functions and should be considered immunosuppressive. n-3 PUFA induced production of resolution molecules is inconsistent with many resolution molecules failing to respond to n-3 PUFA supplementation. n-3 PUFA supplementation is associated with increased lipid peroxidation in most studies. Vitamin E co-administration is unreliable for prevention of the lipid peroxidation. These effects should be considered when administering n-3 PUFA to patients that may be immunosuppressed or under high oxidative stress due to illness or other treatments.
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Barker, Grant, Christiaan Leeuwenburgh, Todd Brusko, Lyle Moldawer, Srinivasa T. Reddy, and Faheem W. Guirgis. "Lipid and Lipoprotein Dysregulation in Sepsis: Clinical and Mechanistic Insights into Chronic Critical Illness." Journal of Clinical Medicine 10, no. 8 (April 14, 2021): 1693. http://dx.doi.org/10.3390/jcm10081693.
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In addition to their well-characterized roles in metabolism, lipids and lipoproteins have pleiotropic effects on the innate immune system. These undergo clinically relevant alterations during sepsis and acute inflammatory responses. High-density lipoprotein (HDL) plays an important role in regulating the immune response by clearing bacterial toxins, supporting corticosteroid release, decreasing platelet aggregation, inhibiting endothelial cell apoptosis, reducing the monocyte inflammatory response, and inhibiting expression of endothelial cell adhesion molecules. It undergoes quantitative as well as qualitative changes which can be measured using the HDL inflammatory index (HII). Pro-inflammatory, or dysfunctional HDL (dysHDL) lacks the ability to perform these functions, and we have also found it to independently predict adverse outcomes and organ failure in sepsis. Another important class of lipids known as specialized pro-resolving mediators (SPMs) positively affect the escalation and resolution of inflammation in a temporal fashion. These undergo phenotypic changes in sepsis and differ significantly between survivors and non-survivors. Certain subsets of sepsis survivors go on to have perilous post-hospitalization courses where this inflammation continues in a low grade fashion. This is associated with immunosuppression in a syndrome of persistent inflammation, immunosuppression, and catabolism syndrome (PICS). The continuous release of tissue damage-related patterns and viral reactivation secondary to immunosuppression feed this chronic cycle of inflammation. Animal data indicate that dysregulation of endogenous lipids and SPMs play important roles in this process. Lipids and their associated pathways have been the target of many clinical trials in recent years which have not shown mortality benefit. These results are limited by patient heterogeneity and poor animal models. Considerations of sepsis phenotypes and novel biomarkers in future trials are important factors to be considered in future research. Further characterization of lipid dysregulation and chronic inflammation during sepsis will aid mortality risk stratification, detection of sepsis, and inform individualized pharmacologic therapies.
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Shang, Pei, Ying Zhang, Di Ma, Yulei Hao, Xinyu Wang, Meiying Xin, Yunhai Zhang, Mingqin Zhu, and Jiachun Feng. "Inflammation resolution and specialized pro-resolving lipid mediators in CNS diseases." Expert Opinion on Therapeutic Targets 23, no. 11 (November 2, 2019): 967–86. http://dx.doi.org/10.1080/14728222.2019.1691525.
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Kraft, Jamie D., Robert Blomgran, Iben Lundgaard, Marianne Quiding-Järbrink, Jonathan S. Bromberg, and Emma Börgeson. "Specialized Pro-Resolving Mediators and the Lymphatic System." International Journal of Molecular Sciences 22, no. 5 (March 9, 2021): 2750. http://dx.doi.org/10.3390/ijms22052750.
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Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.
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Jordan, Paul M., Jana Gerstmeier, Simona Pace, Rossella Bilancia, Zhigang Rao, Friedemann Börner, Laura Miek, et al. "Staphylococcus aureus-Derived α-Hemolysin Evokes Generation of Specialized Pro-resolving Mediators Promoting Inflammation Resolution." Cell Reports 33, no. 2 (October 2020): 108247. http://dx.doi.org/10.1016/j.celrep.2020.108247.
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Recchiuti, Antonio, Elisa Isopi, Mario Romano, and Domenico Mattoscio. "Roles of Specialized Pro-Resolving Lipid Mediators in Autophagy and Inflammation." International Journal of Molecular Sciences 21, no. 18 (September 10, 2020): 6637. http://dx.doi.org/10.3390/ijms21186637.
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Autophagy is a catabolic pathway that accounts for degradation and recycling of cellular components to extend cell survival under stress conditions. In addition to this prominent role, recent evidence indicates that autophagy is crucially involved in the regulation of the inflammatory response, a tightly controlled process aimed at clearing the inflammatory stimulus and restoring tissue homeostasis. To be efficient and beneficial to the host, inflammation should be controlled by a resolution program, since uncontrolled inflammation is the underlying cause of many pathologies. Resolution of inflammation is an active process mediated by a variety of mediators, including the so-called specialized pro-resolving lipid mediators (SPMs), a family of endogenous lipid autacoids known to regulate leukocyte infiltration and activities, and counterbalance cytokine production. Recently, regulation of autophagic mechanisms by these mediators has emerged, uncovering unappreciated connections between inflammation resolution and autophagy. Here, we summarize mechanisms of autophagy and resolution, focusing on the contribution of autophagy in sustaining paradigmatic examples of chronic inflammatory disorders. Then, we discuss the evidence that SPMs can restore dysregulated autophagy, hypothesizing that resolution of inflammation could represent an innovative approach to modulate autophagy and its impact on the inflammatory response.
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Al-Shaer, Abrar E., Nicole Buddenbaum, and Saame Raza Shaikh. "Polyunsaturated fatty acids, specialized pro-resolving mediators, and targeting inflammation resolution in the age of precision nutrition." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1866, no. 7 (July 2021): 158936. http://dx.doi.org/10.1016/j.bbalip.2021.158936.
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Koltsida, Ourania, Sergey Karamnov, Katerina Pyrillou, Thad Vickery, Aikaterini‐Dimitra Chairakaki, Constantin Tamvakopoulos, Paschalis Sideras, Charles N. Serhan, and Evangelos Andreakos. "Toll‐like receptor 7 stimulates production of specialized pro‐resolving lipid mediators and promotes resolution of airway inflammation." EMBO Molecular Medicine 5, no. 5 (April 15, 2013): 762–75. http://dx.doi.org/10.1002/emmm.201201891.
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Fernández-Velasco, María, Silvia González-Ramos, and Lisardo Boscá. "Involvement of monocytes/macrophages as key factors in the development and progression of cardiovascular diseases." Biochemical Journal 458, no. 2 (February 14, 2014): 187–93. http://dx.doi.org/10.1042/bj20131501.
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Emerging evidence points to the involvement of specialized cells of the immune system as key drivers in the pathophysiology of cardiovascular diseases. Monocytes are an essential cell component of the innate immune system that rapidly mobilize from the bone marrow to wounded tissues where they differentiate into macrophages or dendritic cells and trigger an immune response. In the healthy heart a limited, but near-constant, number of resident macrophages have been detected; however, this number significantly increases during cardiac damage. Shortly after initial cardiac injury, e.g. myocardial infarction, a large number of macrophages harbouring a pro-inflammatory profile (M1) are rapidly recruited to the cardiac tissue, where they contribute to cardiac remodelling. After this initial period, resolution takes place in the wound, and the infiltrated macrophages display a predominant deactivation/pro-resolution profile (M2), promoting cardiac repair by mediating pro-fibrotic responses. In the present review we focus on the role of the immune cells, particularly in the monocyte/macrophage population, in the progression of the major cardiac pathologies myocardial infarction and atherosclerosis.
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Quiros, Miguel, Darius Feier, Dorothee Birkl, Rachit Agarwal, Dennis W. Zhou, Andrés J. García, Charles A. Parkos, and Asma Nusrat. "Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing." Proceedings of the National Academy of Sciences 117, no. 17 (April 16, 2020): 9477–82. http://dx.doi.org/10.1073/pnas.1921335117.
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Resolution of intestinal inflammation and wound repair are active processes that mediate epithelial healing at mucosal surfaces. Lipid molecules referred to as specialized proresolving mediators (SPMs) play an important role in the restorative response. Resolvin E1 (RvE1), a SPM derived from omega-3 fatty acids, has been reported to dampen intestinal inflammation by promoting anti-inflammatory responses including increased neutrophil spherocytosis and macrophage production of IL-10. Despite these observations, a role for RvE1 in regulating intestinal epithelial cell migration and proliferation during mucosal wound repair has not been explored. Using an endoscopic biopsy-based wound healing model, we report that RvE1 is locally produced in response to intestinal mucosal injury. Exposure of intestinal epithelial cells to RvE1 promoted wound repair by increasing cellular proliferation and migration through activation of signaling pathways including CREB, mTOR, and Src-FAK. Additionally, RvE1-triggered activation of the small GTPase Rac1 led to increased intracellular reactive oxygen species (ROS) production, cell–matrix adhesion, and cellular protrusions at the leading edge of migrating cells. Furthermore, in situ administration of RvE1-encapsulated synthetic targeted polymeric nanoparticles into intestinal wounds promoted mucosal repair. Together, these findings demonstrate that RvE1 functions as a prorepair lipid mediator by increasing intestinal epithelial cell migration and proliferation, and highlight potential therapeutic applications for this SPM to promote mucosal healing in the intestine.
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Miyazawa, Keishi, Hisanori Fukunaga, Yasuko Tatewaki, Yumi Takano, Shuzo Yamamoto, Tatsushi Mutoh, and Yasuyuki Taki. "Alzheimer’s Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?" International Journal of Molecular Sciences 21, no. 16 (August 12, 2020): 5783. http://dx.doi.org/10.3390/ijms21165783.
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Alzheimer’s disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it—i.e., specialized pro-resolving lipid mediators (SPMs)—attracted attention in recent years as therapeutic targets. This review focuses on the following three specific SPMs and summarizes their relationships to AD, as they were shown to effectively address and reduce the risk of AD-related neuroinflammation: maresin 1 (MaR1), resolvin D1 (RvD1), and neuroprotectin D1 (NPD1). These three SPMs are metabolites of docosahexaenoic acid (DHA), which is contained in fish oils and is thus easily available to the public. They are expected to become incorporated into promising avenues for preventing and treating AD in the future.
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Johnson, Louise A., and David G. Jackson. "Hyaluronan and Its Receptors: Key Mediators of Immune Cell Entry and Trafficking in the Lymphatic System." Cells 10, no. 8 (August 12, 2021): 2061. http://dx.doi.org/10.3390/cells10082061.
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Entry to the afferent lymphatics marks the first committed step for immune cell migration from tissues to draining lymph nodes both for the generation of immune responses and for timely resolution of tissue inflammation. This critical process occurs primarily at specialised discontinuous junctions in initial lymphatic capillaries, directed by chemokines released from lymphatic endothelium and orchestrated by adhesion between lymphatic receptors and their immune cell ligands. Prominent amongst the latter is the large glycosaminoglycan hyaluronan (HA) that can form a bulky glycocalyx on the surface of certain tissue-migrating leucocytes and whose engagement with its key lymphatic receptor LYVE-1 mediates docking and entry of dendritic cells to afferent lymphatics. Here we outline the latest insights into the molecular mechanisms by which the HA glycocalyx together with LYVE-1 and the related leucocyte receptor CD44 co-operate in immune cell entry, and how the process is facilitated by the unusual character of LYVE-1 • HA-binding interactions. In addition, we describe how pro-inflammatory breakdown products of HA may also contribute to lymphatic entry by transducing signals through LYVE-1 for lymphangiogenesis and increased junctional permeability. Lastly, we outline some future perspectives and highlight the LYVE-1 • HA axis as a potential target for immunotherapy.
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Yang, Ailin, Yanjun Wu, Ganggang Yu, and Haoyan Wang. "Role of specialized pro-resolving lipid mediators in pulmonary inflammation diseases: mechanisms and development." Respiratory Research 22, no. 1 (July 14, 2021). http://dx.doi.org/10.1186/s12931-021-01792-y.
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AbstractInflammation is an essential mechanism of various diseases. The development and resolution of inflammation are complex immune-modulation processes which induce the involvement of various types of immune cells. Specialized pro-resolving lipid mediators (SPMs) have been demonstrated to be signaling molecules in inflammation. SPMs are involved in the pathophysiology of different diseases, especially respiratory diseases, including asthma, pneumonia, and chronic obstructive pulmonary disease. All of these diseases are related to the inflammatory response and its persistence. Therefore, a deeper understanding of the mechanisms and development of inflammation in respiratory disease, and the roles of the SPM family in the resolution process, might be useful in the quest for novel therapies and preventive measures for pulmonary diseases.
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Zaninelli, Tiago H., Victor Fattori, and Waldiceu A. Verri. "Harnessing Inflammation Resolution in Arthritis: Current Understanding of Specialized Pro-resolving Lipid Mediators’ Contribution to Arthritis Physiopathology and Future Perspectives." Frontiers in Physiology 12 (September 1, 2021). http://dx.doi.org/10.3389/fphys.2021.729134.
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The concept behind the resolution of inflammation has changed in the past decades from a passive to an active process, which reflects in novel avenues to understand and control inflammation-driven diseases. The time-dependent and active process of resolution phase is orchestrated by the endogenous biosynthesis of specialized pro-resolving lipid mediators (SPMs). Inflammation and its resolution are two forces in rheumatic diseases that affect millions of people worldwide with pain as the most common experienced symptom. The pathophysiological role of SPMs in arthritis has been demonstrated in pre-clinical and clinical studies (no clinical trials yet), which highlight their active orchestration of disease control. The endogenous roles of SPMs also give rise to the opportunity of envisaging these molecules as novel candidates to improve the life quality of rhematic diseases patients. Herein, we discuss the current understanding of SPMs endogenous roles in arthritis as pro-resolutive, protective, and immunoresolvent lipids.
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Livshits, Gregory, and Alexander Kalinkovich. "Specialized, Pro-Resolving Mediators as Potential Therapeutic Agents for Alleviating Fibromyalgia Symptomatology." Pain Medicine, February 10, 2021. http://dx.doi.org/10.1093/pm/pnab060.
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Abstract Objective To present a hypothesis on a novel strategy in the treatment of fibromyalgia (FM). Design A narrative review. Setting FM as a disease remains a challenging concept for numerous reasons, including undefined etiopathogenesis, unclear triggers, and unsuccessful treatment modalities. We hypothesize that the inflammatome, the entire set of molecules involved in inflammation, acting as a common pathophysiological instrument of gut dysbiosis, sarcopenia, and neuroinflammation, is one of the major mechanisms underlying FM pathogenesis. In this setup, dysbiosis is proposed as the primary trigger of the inflammatome, sarcopenia as the peripheral nociceptive source, and neuroinflammation as the central mechanism of pain sensitization, transmission, and symptomatology of FM. Whereas neuroinflammation is highly considered as a critical deleterious element in FM pathogenesis, the presumed pathogenic roles of sarcopenia and systemic inflammation remain controversial. Nevertheless, sarcopenia-associated processes and dysbiosis have been recently detected in individuals with FM. The prevalence of pro-inflammatory factors in the cerebrospinal fluid and blood has been repeatedly observed in individuals with FM, which supports the idea of a role of the inflammatome in FM pathogenesis. As such, failed inflammation resolution might be one of the underlying pathogenic mechanisms. Accordingly, the application of specialized, inflammation pro-resolving mediators (SPMs) seems most suitable for this goal. Conclusions The capability of various SPMs to prevent and attenuate pain has been repeatedly demonstrated in laboratory animal experiments. As SPMs suppress inflammation in a manner that does not compromise host defense, they could be attractive and safe candidates for the alleviation of FM symptomatology, probably in combination with anti-dysbiotic medicine.
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Hasturk, Hatice, Fabian Schulte, Melissa Martins, Homa Sherzai, Constantinos Floros, MaryAnn Cugini, Chung-Jung Chiu, Markus Hardt, and Thomas Van Dyke. "Safety and Preliminary Efficacy of a Novel Host-Modulatory Therapy for Reducing Gingival Inflammation." Frontiers in Immunology 12 (September 13, 2021). http://dx.doi.org/10.3389/fimmu.2021.704163.
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BackgroundPeriodontal disease is among the sixth most common inflammatory diseases worldwide with high risk to promote complications from other inflammatory diseases including diabetes, cardiovascular disease and Alzheimer’s Disease. Failure of active resolution of inflammation pathways is implicated in pathogenesis of periodontal diseases, including gingivitis. Lipoxin A4 (LXA4), a member of the specialized pro-resolving lipid mediators (SPMs) that drive resolution of inflammation via GPC-receptor mediated pathways, offered therapeutic advantages in preclinical models of periodontitis.MethodsWe conducted a randomized, placebo-controlled, parallel-group Phase 1 clinical trial to determine the safety and preliminary efficacy of an LXA4 analog in patients with gingival inflammation. One hundred twenty-seven (127) individuals were randomized to daily use of an oral rinse containing a LXA4 mimetic, methyl ester-benzo-lipoxin A4 (BLXA4), placebo rinse or a no-rinse control group for 28 days. Treatment emergent adverse events (TEAEs) were assessed for safety, the primary outcome. Secondary outcomes included the change in the level of gingival inflammation and periodontal pocket depth (PD). Serum SPMs were monitored using targeted lipid mediator lipidomics to assess potential systemic impact of BLXA4.ResultsThe frequency of TEAEs was similar in BLXA4 and placebo-treated groups with no study-related SAEs. Once-daily rinsing with BLXA4 for 28-days resulted in a greater decrease in gingival inflammation compared to placebo rinse and no-rinse control groups (mean change: 0.26 GI unit vs 0.21 and 0.17, respectively). PD reduction was also greater with BLXA4 oral rinse compared to placebo and no-rinse groups (mean reduction: 1.23 mm vs. 0.71 mm and 0.46 mm, respectively). Topical application of BLXA4 increased serum levels of SPMs.ConclusionTreatment with BLXA4 reduces local inflammation, and increases abundance of pro-resolution molecules systemically, which may dampen inflammation that can mediate progression and course of inflammatory diseases beyond periodontitis.Clinical Trial RegistrationClinicalTrials.gov, identifier (NCT02342691).
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Miyahara, Takuya, Anuran Chatterjee, Mian Chen, Sara Runge, and Michael S. Conte. "Abstract 222: D-Series Resolvins Modulate Postinjury Signaling Pathways in Vascular Smooth Muscle Cells." Arteriosclerosis, Thrombosis, and Vascular Biology 32, suppl_1 (May 2012). http://dx.doi.org/10.1161/atvb.32.suppl_1.a222.
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Introduction: Recent work suggests that the resolution of inflammation is an active process involving specialized molecules that are locally generated. D-series resolvins (RvD) are endogenous pro-resolving lipid mediators derived from the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA). VSMC activation following vascular injury leads to neointimal hyperplasia which may reflect a relative “resolution deficit” in the vessel wall. Objectives: We sought to determine the effects of RvD on injury-related inflammatory and growth factor signaling pathways in VSMC, using in vitro and in vivo models. Hypothesis: We hypothesize that RvD will attenuate VSMC activation responses and modulate vascular injury. Methods: Human VSMC were treated with cytokines (TNF-α, IL-1β), growth factors (PDGF, AngII) or oxidant stress (H 2 O 2 ) in the presence of RvD1 or RvD2 (.01-100 nM), and phenotype was assessed by cytotoxicity, proliferation, migration (transwell), monocyte adhesion (U937) and adhesion molecule expression (qPCR and flow cytometry) assays. NZW rabbits (N=4) underwent bilateral femoral balloon injury with intraluminal delivery of RvD2 (10 nM vs vehicle control) to examine acute effects (3 days) on the injury response. Results: RvD treatment of VSMC produced dose-dependent inhibition of VSMC proliferation (max %inhibition: RvD1 58.8%, p<0.01, RvD2 63.1%, p<0.01), migration (RvD1 66.1%, p<0.01%, RvD2 68.8%, p<0.01), monocyte adhesion (RvD1 36.0%, p<0.01, RvD2 41.0%, p<0.01), and inducible adhesion molecule expression (VCAM-1: RvD1 70.5%, p<0.01, RvD2 77.2%, p<0.01; ICAM-1: RvD1 65.4%, p<0.01, RvD2 72.1%, p<0.01) without measurable cytotoxicity. In the rabbit model of balloon arterial injury, proliferation was significantly reduced at 3 days in RvD2 treated vessels (%inhibition 57%, p<0.01). Conclusion: RvD broadly inhibit VSMC activation responses and may modulate the vascular injury response in-vivo .
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Leuti, Alessandro, Marina Fava, Niccolò Pellegrini, and Mauro Maccarrone. "Role of Specialized Pro-Resolving Mediators in Neuropathic Pain." Frontiers in Pharmacology 12 (August 11, 2021). http://dx.doi.org/10.3389/fphar.2021.717993.
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Inflammation and neuroinflammation are critical mechanisms in the generation of neuropathic pain that is experienced in several chronic diseases. The aberrant inflammation that triggers this pathophysiologic process can be tracked down to an exacerbated immune response, which establishes a vicious cycle and continuously recruits inflammatory cells by inducing chronic tissue damage. Recently, impairment of the cellular and molecular machinery orchestrated by specialized pro-resolving mediators (SPMs)—i.e., endogenous lipids termed resolvins, protectins, maresins, and lipoxins that confine the inflammatory cascades in space and time during the “resolution of inflammation”–has emerged as a crucial event in the derangement of the inflammatory homeostasis and the onset of chronic inflammation and pain. Indeed, a deviant inflammatory response that is not adequately controlled by the resolution network leads to the overproduction of pro-inflammatory eicosanoids that, opposite to SPMs, lead to neuropathic pain. Interestingly, in the last two decades convincing evidence has demonstrated that SPMs antagonize the in vivo activity of pro-inflammatory eicosanoids and, overall, exert potent anti-hyperalgesic effects in a number of pain-associated paradigms of disease, such as arthritis and chemotherapy-induced peripheral neuropathy, as well as in many experimental models of pain like mechanical allodynia, chemical pain, heat hypersensitivity and phase 1 and 2 inflammatory pain. Of note, accumulated evidence supports a synergy between SPMs and other signalling pathways, such as those mediated by transient receptor potential (TRP) channels and those triggered by opioid receptors, suggesting that the cascade of events where inflammation and pain perception take part might be ways more intricated than originally expected. Here, we aim at presenting a state-of-the-art view of SPMs, their metabolism and signalling, in the context of cellular and molecular pathways associated to neuropathic pain.
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Balta, Maria G., Evangelos Papathanasiou, and Panagiotis F. Christopoulos. "Specialized Pro-Resolving Mediators as Potential Regulators of Inflammatory Macrophage Responses in COVID-19." Frontiers in Immunology 12 (February 24, 2021). http://dx.doi.org/10.3389/fimmu.2021.632238.
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The recent outbreak of SARS-CoV2 has emerged as one of the biggest pandemics of our century, with outrageous health, social and economic consequences globally. Macrophages may lay in the center of COVID-19 pathogenesis and lethality and treatment of the macrophage-induced cytokine storm has emerged as essential. Specialized pro-resolving mediators (SPMs) hold strong therapeutic potentials in the management of COVID-19 as they can regulate macrophage infiltration and cytokine production but also promote a pro-resolving macrophage phenotype. In this review, we discuss the homeostatic functions of SPMs acting directly on macrophages on various levels, towards the resolution of inflammation. Moreover, we address the molecular events that link the lipid mediators with COVID-19 severity and discuss the clinical potentials of SPMs in COVID-19 immunotherapeutics.
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Lumbroso, Delphine, Soaad Soboh, Avi Maimon, Sagie Schif-Zuck, Amiram Ariel, and Tal Burstyn-Cohen. "Macrophage-Derived Protein S Facilitates Apoptotic Polymorphonuclear Cell Clearance by Resolution Phase Macrophages and Supports Their Reprogramming." Frontiers in Immunology 9 (March 1, 2018). http://dx.doi.org/10.3389/fimmu.2018.00358.
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The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells (PMN) by local macrophages (efferocytosis) and the consequent reprogramming of the engulfing phagocytes to reparative and pro-resolving phenotypes. The tyrosine kinase receptors TYRO3, AXL, and MERTK (collectively named TAM) are fundamental mediators in regulating inflammatory responses and efferocytosis. Protein S (PROS1) is a ligand for all TAM receptors that mediates various aspects of their activity. However, the involvement of PROS1 in the resolution of inflammation is incompletely understood. Here, we report the upregulation of Pros1 in macrophages during the resolution of inflammation. Selective knockout of Pros1 in the myeloid lineage significantly downregulated macrophage pro-resolving properties. Hence, Pros1-deficient macrophages engulfed fewer apoptotic PMN remnants in vivo, and exogenous PROS1 rescued impaired efferocytosis ex vivo. Moreover, Pros1-deficient peritoneal macrophages secreted higher levels of the pro-inflammatory mediators TNFα and CCL3, while they secreted lower levels of the reparative/anti-inflammatory IL-10 following exposure to lipopolysaccharide in comparison to their WT counterparts. Moreover, Pros1-deficient macrophages expressed less of the anti-inflammatory/pro-resolving enzymes arginase-1 and 12/15-lipoxygenase and produced less of the specialized pro-resolving mediator resolvin D1. Altogether, our results suggest that macrophage-derived PROS1 is an important effector molecule in regulating the efferocytosis, maturation, and reprogramming of resolution phase macrophages, and imply that PROS1 could provide a new therapeutic target for inflammatory and fibrotic disorders.
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Tiberi, Marta, and Valerio Chiurchiù. "Specialized Pro-resolving Lipid Mediators and Glial Cells: Emerging Candidates for Brain Homeostasis and Repair." Frontiers in Cellular Neuroscience 15 (April 26, 2021). http://dx.doi.org/10.3389/fncel.2021.673549.
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Astrocytes and oligodendrocytes are known to play critical roles in the central nervous system development, homeostasis and response to injury. In addition to their well-defined functions in synaptic signaling, blood-brain barrier control and myelination, it is now becoming clear that both glial cells also actively produce a wide range of immune-regulatory factors and engage in an intricate communication with neurons, microglia or with infiltrated immune cells, thus taking a center stage in both inflammation and resolution processes occurring within the brain. Resolution of inflammation is operated by the superfamily of specialized pro-resolving lipid mediators (SPMs), that include lipoxins, resolvins, protectins and maresins, and that altogether activate a series of cellular and molecular events that lead to spontaneous regression of inflammatory processes and restoration of tissue homeostasis. Here, we review the manifold effects of SPMs on modulation of astrocytes and oligodendrocytes, along with the mechanisms through which they either inhibit inflammatory pathways or induce the activation of protective ones. Furthermore, the possible role of SPMs in modulating the cross-talk between microglia, astrocytes and oligodendrocytes is also summarized. This SPM-mediated mechanism uncovers novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and neurodegeneration.
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Zhao, Xiurong, Guanghua Sun, Shun-Ming Ting, and Jaroslaw Aronowski. "Abstract WP98: Role of Hydrogen Peroxide in Preconditioning of Microglia to Achieve Improved Hematoma Cleanup After ICH." Stroke 48, suppl_1 (February 2017). http://dx.doi.org/10.1161/str.48.suppl_1.wp98.
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Background: Red blood cells ( RBC ) and other blood components deposited in brain parenchyma during intracerebral hemorrhage ( ICH ) are the source of secondary brain injury, inflammation, and oxidative stress. Therefore, a fast and efficient removal of the blood from the brain is essential for ameliorating secondary injury and for recovery and repair process. Microglia/macrophages ( MΦ )-mediated phagocytosis is a key component of hematoma clearance after ICH. However, the high levels of pro-oxidative molecules (including H 2 O 2 ) generated by MΦ during phagocytosis could be highly cytotoxic not only to brain cells, but also to MΦ themselves. Thus, an efficient coupling between MΦ-mediated phagocytosis and anti-oxidative processes is essential for the safe and efficient hematoma cleanup. Methods and Results: H 2 O 2 at higher concentrations is known to be neurotoxic. In this study, we established that H 2 O 2 at submicromolar, biologically relevant concentrations, acts as a pro-survival factor for MΦ. By activating transcription factor nuclear factor-erythroid 2 p45-related factor 2 ( Nrf2 ), a master regulator of anti-oxidative regulation, H 2 O 2 stimulates the expression of many antioxidant proteins, which protects MΦ from oxidative injury and damaging components of inflammation. We established that Nrf2-deficient MΦ are more susceptible to H 2 O 2 -mediated or toxic blood components-mediated damage (“ICH-like” injury). Nrf2-KO mice subjected to ICH experienced more severe brain edema and delayed hematoma resolution. In addition, the phagocytosis of RBCs (in vitro model of hematoma clearance) was significantly diminished in MΦ treated with Nrf2 decoy or in MΦ that were harvested from Nrf2-KO mice. On the other hand, pharmacologic activation of Nrf2 or administration of low dosages of H 2 O 2 improved phagocytic capacity of MΦ toward RBC. Furthermore, low levels of H 2 O 2 protected MΦ from ICH-like injury, suggesting that improved phagocytic function could involve preservation of MΦ’ integrity by activating Nrf2. Conclusion: H 2 O 2 at low doses could protect MΦ for oxidative injury and facilitate their phagocytic function, which could benefit hematoma clearance, inflammation resolution, and improve neurological recovery after ICH.