Nature 461, 12871291 (2009). Brezinski, M. E., Gimbrone, M. A. Jr, Nicolaou, K. C. & Serhan, C. N. Lipoxins stimulate prostacyclin generation by human endothelial cells. 3, 270279 (2010). Natl Acad. Specialized pro-resolving mediators: endogenous regulators of infection and inflammation. Mucosal Immunol. Bruce D. Levy. Immun. Both tissue-resident and recruited inflammatory macrophages serve pivotal roles in responses to infection and inflammation. Similarly to 15-epi-lipoxins, resolvins are generated through interactions between aspirin-acetylated COX2 and LOX activities39. Because SPMs act at these pain receptors in the nervous system and on inflammatory pathways, these findings suggest that regulation of sensory neuron activation could be a crucial mechanism for SPM inhibition of both pain and lung inflammation. Host responses to RSV again highlight roles for SPMs and lipid mediator class-switching in the initial control and eventual clearance of infection. & Fiore, S. Lipoxin A4 inhibits IL-1-induced IL-6, IL-8, and matrix metalloproteinase-3 production in human synovial fibroblasts and enhances synthesis of tissue inhibitors of metalloproteinases. Biol. 193, 60316040 (2014). As discussed above, preclinical data for bacterial infection points to important and pivotal roles for lipid mediators, in particular SPMs, in the regulation of host responses to infection12,13 with the potential for host SPM-directed interventions to decrease antibiotic requirements12,95.
Pro-resolving lipid mediators: regulators of inflammation - Nature Sci. 178, 496502 (2007). Serhan, C. N. et al. 7, 12091216 (2006). Lipoxins are formed by transcellular biosynthesis via multiple distinct pathways. Clinical trials with SPM analogues that resist metabolic inactivation are still in early phases. Biol. Levy, B. D. et al. Hellmann, J., Tang, Y., Kosuri, M., Bhatnagar, A. Molofsky, A. Am. Diabetes 62, 19451956 (2013). Nat. Lipoxins are potential endogenous anti-inflammatory mediators in asthma. This report highlights the balance between pro-inflammatory and pro-resolving mediators in the clearance of M. tuberculosis infection. Fibrotic lung disease. In contrast to neutrophils, SPMs lead to macrophage shape changes that prepare the cells for phagocytosis of microorganisms, apoptotic cells and debris9,12,62,63. 287, 779790 (1998). Nat. Cell 153, 112125 (2013).
Specialized proresolving mediators: biosynthesis and biological role 5, 698701 (1999). CAS Invest. J. Physiol. The SPM precursors eicosapentaenoic acid and docosahexaenoic acid are essential omega-3 PUFAs. Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification. J. Neurosci. J. Immunol. These are distinct from other immune-system signaling molecules not only in their composition . Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. 180, 311319 (2009). Natural killer (NK) cells can help promote the resolution of an inflammatory response by inducing neutrophil66 and eosinophil apoptosis67, which is a non-inflammatory mechanism for cell removal from tissues and has a crucial role in successful resolution of the inflammatory response8. J. Biol. Shirey, K. A. et al. Of note, MaR1 was recently identified as a potent inducer for the formation of regulatory T cells in vivo and in vitro in combination with TGF70. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. 53, 160171 (2012).
Specialized pro-resolving mediators in cardiovascular diseases J. Exp. Sepsis is a disease of overwhelming infectious insult, compounded by an overly robust inflammatory response, whereby treatment with anti-inflammatory therapies potentially subjects the host to further harm. Members of the growing new genus of SPMs or their bioactive stable analogues represent potential candidates to harness endogenous anti-inflammatory resolution mechanisms to limit overly exuberant pathogen-mediated inflammation in future therapeutic strategies. Natl Acad. With Toxoplasma gondii, there is a robust DC response with production of IL-12 (Ref. Allergy 49, 230234 (1994). FASEB J. Specialized pro-resolving mediators (SPMs) are enzymatically derived from essential fatty acids to serve as a novel class of immunoresolvents that limit acute responses and orchestrate the clearance of tissue pathogens, dying cells and debris from the battlefield of infectious inflammation. J. Immunol. During a self-limited inflammatory response, resolution of inflammation is an active process governed by specialized pro-resolving mediators (SPMs) that transmit both anti-inflammatory (red) and pro-resolving (blue) actions to leukocytes and tissue-resident cells. Typically, acute inflammatory responses to pathogens are self-limiting, and there is a growing appreciation that SPMs have pivotal anti-inflammatory and anti-infective roles in tissue catabasis4. Nascimento-Silva, V., Arruda, M. A., Barja-Fidalgo, C. & Fierro, I. M. Aspirin-triggered lipoxin A4 blocks reactive oxygen species generation in endothelial cells: a novel antioxidative mechanism. The generation of SPMs may not always be beneficial to the host. Ther. In this Review, we address the functions of SPMs in infectious immunity and chronic inflammatory diseases, with a focus on how SPMs affect lung physiology and pathology in these diseases. These include resolvins, protectins and maresins (reviewed in Ref. Sci. J. Pharmacol. Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation. PubMed Pulmonary antifibrotic mechanisms aspirin-triggered lipoxin A4 synthetic analog. Med. 1, 25-dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid- phagocytosis and inflammation in Alzheimer's disease patients. Sci. Asthma and allergic inflammation. Medeiros, R. et al. J. Immunol. Proc. Focusing on fundamental mechanisms in the resolution responses, the authors' laboratory uncovered several novel families of pro-resolving lipid mediators (LM) of inflammation that are biosynthesized from essential polyunsaturated fatty acid precursors, e.g. Haworth, O., Cernadas, M., Yang, R., Serhan, C. N. & Levy, B. D. Resolvin E1 regulates interleukin 23, interferon- and lipoxin A4 to promote the resolution of allergic airway inflammation. Synonyms Immunoresolvents; Specialized pro-resolving lipid mediators; SPMs Definition Pro-resolving mediators are endogenous signaling molecules that act as "stop signals" to terminate an inflammatory reaction when no longer needed to promote the return to a normal tissue state (Serhan 2014 ). With NK cell depletion, the pro-resolving function of RvE1 is partially impaired68. 25, 29672979 (2011). Pro-resolving mediators could represent a novel strategy in a sparse arsenal. Dis. J. Biol. Phagocytic docking without shocking. Am. In this section, we highlight selected cell types with important functions in resolution and host defence that respond to SPMs. 186, 30763084 (2011). Nature 484, 524528 (2012). Pneumonia. Anti-inflammatory role of the murine formyl-peptide receptor 2: ligand-specific effects on leukocyte responses and experimental inflammation. J. Immunol. 34, 155170 (2013). Ariel, A. et al. Counter-regulation of pathogen-mediated inflammation is an active process with specific cellular and biochemical events that are tightly regulated in health. Biochem. J. Exp. J. Immunol. Finally, we consider how new therapeutic strategies that incorporate immunoresolvents may have the potential to synergize with antibiotics and to mitigate the growing problem of antibiotic resistance. FASEB J. Ophthalmol. Senthil Kumaran Satyanarayanan, Driss El Kebir, Amiram Ariel, Kadi J. Horn, Melissa A. Schopper, Sarah E. Clark, Hisanori Domon, Tomoki Maekawa, Yutaka Terao, Meng-Li Wu, Feng-Liang Liu, Jian-Hua Wang, Catherine J. Greene, Jenny A. Nguyen, Robin M. Yates, E. Letsiou, L. G. Teixeira Alves, M. Witzenrath, Nature Reviews Immunology Google Scholar. Nat Rev Immunol 16, 5167 (2016). USA 111, 1652616531 (2014). Nat. The ability to clear the source of infection while still limiting the immune response provides an attractive therapeutic paradigm for this disease of substantial health-care burden. J. Exp. This study shows that SPM actions increase clearance of E. coli and decrease host inflammation to enhance survival. CAS 38) (Fig. Med. Med. Care Med. Sun, Y. P. et al. This study identifies new cellular mechanisms for SPMs to regulate innate lymphoid cell responses, such as NK cell-mediated granulocyte apoptosis and regulation of ILC2 cytokine release. Role of the lipoxygenase pathway in RSV-induced alternatively activated macrophages leading to resolution of lung pathology. Immunol. Treatment of septic mice with RvD2 leads to a profound reduction in the production of cytokines, including IL-6, IL-10 and interferon- (IFN), and leukocyte infiltration to the site of infection is reduced. Treatment with MaR1 is organ protective and limits the extent of lung inflammation. Natl Acad. Immunol. 174, 43454355 (2005). More virulent strains of influenza led to suppression of lipoxins98, which is associated with enhanced viral dissemination. In light of the current serious threat of emerging pathogens, in particular those that display antibiotic resistance, the development of therapies to augment host anti-infective mechanisms are needed. 64). Palmer, C. D. et al. Park, C. K. et al. The lta4h locus modulates susceptibility to mycobacterial infection in zebrafish and humans. Resolvins are produced fo J. Immunol. Commun. Multiple pulmonary injurious exposures have a unifying endpoint in the development of extensive tissue scarring, resulting in poor gas exchange, air movement and demise of the host. This class of endogenous immunoresolvents induces an anti-inflammatory response by inhibiting granulocyte migration and activation, disrupting sensory neuron activation and dampening cytokine production by a variety of structural cells, including epithelial cells, endothelial cells and fibroblasts. Sci. In Escherichia coli-induced pneumonia, the SPM LXA4 promotes neutrophil apoptosis by inducing the phosphorylation of BCL-2-associated death promoter (BAD) and reducing the expression of the anti-apoptotic protein myeloid cell leukaemia sequence 1 (MCL1)80, whereas RvE1 promotes neutrophil apoptosis through activation of caspases81. 164, 278293 (2011). Cell 140, 717730 (2010). 176, 18481859 (2006). Rajasagi, N. K. et al. Takamiya, R. et al. Similarly, protectin D1 has been shown to promote resolution of the lung inflammatory response and block airway hyperresponsiveness47. These SPMs exert their bioactions as molecular signals via agonist properties at cognate receptors (Fig. In addition, SPMs promote decay accelerating factor expression in mucosal epithelia as well as expression of the anti-infective peptide bactericidal permeability-increasing protein and the lipopolysaccharide (LPS) detoxification enzyme alkaline phosphatase78,79. Med. J. Med. Godson, C. et al. Proc. New Engl. J. Immunol. These examples further illustrate the delicate balance between the pathogen and the host in SPM production and control of host immune responses. Imai, Y. 182, 17801789 (2013). Jain, A. et al. Proc. J. Alzheimer's Dis. Allergy Clin. 156, 22642272 (1996). Maddox, J. F. & Serhan, C. N. Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. FASEB J. J. Immunol. Neuron 87, 341354 (2015). Serhan, C. N., Hamberg, M. & Samuelsson, B. Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. Med. Slider with three articles shown per slide. Reis e Sousa, C. et al. Cornea 31, 12991303 (2012). To characterize the effects of SPMs on tissue regeneration, the planarian tissue self-repair model was mainly . Sulfido-Conjugates of Specialized Pro-Resolving Mediators. Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion. he authors wish to acknowledge C. N. Serhan for his helpful advice in the preparation of this manuscript. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Connor, K. M. et al. Cell 154, 213227 (2013). Nat. In hosts infected with influenza viruses, endogenous protectin D1 production is increased. Serhan, C. N., Arita, M., Hong, S. & Gotlinger, K. Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their endogenous aspirin-triggered epimers. Crit. In addition to T. gondii, the opportunistic bacteria Pseudomonas aeruginosa can express a secreted LOX that can augment SPM production in the local milieu to modulate host defence116. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Freire-de-Lima, C. G. et al. These fatty acid-derived mediators are part of a larger resolution programme that includes annexin A1 protein16, several cytokines (for example, transforming growth factor- (TGF) and interleukin-10 (IL-10))11, microRNAs51 and carbon monoxide56. 184, 26112619 (2010). Proc. Am. In addition, for viral host responses, SPMs lessened the severity of influenza and HSV infections102,107,108. Although the role of SPMs has only recently been uncovered in tissue homeostasis, there is already a push to understand the functions of SPMs in infections. An active process at the cellular and tissue level governed by specific mediators that promote a return to tissue homeostasis. Invest. Int. Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. Nature 447, 869874 (2007). Bowel Dis. Dis. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. RvE1 also acts on cigarette smoke-activated macrophages, reducing superoxide production and limiting inflammation129. J. Clin. & Serhan, C. N. Tonic inhibition of chemotaxis in human plasma. J. Clin. Apoptotic cells, through transforming growth factor-, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. Czerska, K. et al. Many of these SPMs are produced during the acute inflammatory response6, and their structure, biosynthesis and organic synthesis have been recently reviewed (see Ref. Natl Acad. Role for periodontitis in the progression of lipid deposition in an animal model. Functional roles bring these structurally distinct families of lipoxins, resolvins, protectins and maresins together as SPMs a genus of endogenous molecules that pharmacologically act as immunoresolvents4. Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. Crucial roles for arachidonic acid metabolism in immune responses may be linked to the different infectious rates observed with human variants in the ALOX5 (encoding 5-LOX) locus93 and the LTA4H (which encodes LTA4 hydrolase, an enzyme involved in the final step of LTB4 production) locus94, which both appear to disrupt LTB4 and LXA4 production as well as altering protection against naturally occurring M. tuberculosis infection. SPMs are lipid mediators that are part of a larger family of pro-resolving molecules, which includes proteins and gases, that together restrain inflammation and resolve the infection. Hong, S., Gronert, K., Devchand, P. R., Moussignac, R. L. & Serhan, C. N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust.
Can Specialized Pro-resolving Mediators Deliver Benefit - Springer Promotion of these two alternative macrophage fates appears related to RSV-induced COX2 (Ref. 187, 19571969 (2011). 52, 37833791 (2005). This study provides crucial evidence that resolution is an active process and inhibiting SPM formation leads to a 'toxic' resolution. Arita, M. et al.
Specialized Pro-Resolving Mediator Network: An Update on Production and 186, 18191829 (1997). Periodontitis also carries a more generalized implication to human health, as localized periodontitis elicits a systemic response, increasing systemic inflammation and risk for accelerated atherosclerosis82,83. Am. Ramon, S. et al. As a class, the SPMs are enzymatically derived from essential fatty acids, including arachidonic acid, eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3) in a lipoxygenase (LOX)-dependent manner (Fig. Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis. Nat. Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. in the localized aggressive form of the disease. Park, C. K. et al.
Specialized Pro-Resolving Mediators Mitigate Cancer-Related Martins, V. et al. & Spite, M. Resolvin D1 decreases adipose tissue macrophage accumulation and improves insulin sensitivity in obese-diabetic mice. 299, H153H164 (2010). The interests of B.D.L. 210, 535549 (2013). Cell Mol. Immun. J. Pathol. Sordi, R. et al. J. Immunol. 282, 93239334 (2007). https://metagenicsinstitute.com/wp-content/uploads/2021 . Prostaglandin E2 (PGE2) and PGI2 regulate blood flow, whereas leukotriene C4 (LTC4) and LTD4 regulate vascular permeability1,23. Wu, S. H., Chen, X. Q., Liu, B., Wu, H. J. 19, 19501961 (2012). Neuropharmacology 86, 5766 (2014). Med. Aliberti, J., Serhan, C. & Sher, A. Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. Specialized pro-resolving mediators and therapeutic approaches that target these neuroimmune mechanisms are also discussed. Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Am. USA 105, 1794917954 (2008). Lawrence, D. W. et al. 212, 12031217 (2015). Involvement of platelet-endothelial cell adhesion molecule-1 in neutrophil recruitment in vivo. 1/2 #HYPHIP @fjorios. Nat. J. Clin. Pharmacological structure activity relationships support receptor-dependent signalling mechanisms for the remaining SPMs; however, the molecular identity of their cognate receptors is still to be determined. Natl Acad. Monticelli, L. A. et al. 25, 14411448 (2011). Resolution of inflammation is controlled by a group of molecules called specialized pro-resolving mediators, or SPMs. The biological demand for an initial robust response against a bacterial insult is juxtaposed against the need to control prolonged and overly exuberant inflammatory responses that are potentially harmful, raising potential challenges for the therapeutic use of pro-resolving mediators. 1). The role of resolvins in COPD is a subject of active investigation. 7, e2173 (2013). The resolution responses that occur in non-pulmonary sites of infection and inflammation have recently been reviewed (see Refs 7,19,20,21). J. Exp. Once generated, ceramide can act as substrate for other sphingolipids such as sphingosine and . Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease. Levy, B. D. et al. Dufton, N. et al. Adaptive immune cells also have important roles in the active resolution of inflammation. Resolvin E1 and chemokine-like receptor 1 mediate bone preservation. Proc. Granulocytes are rapidly recruited to sites of infection2, where they become activated and augment the resident capacity of infected tissue to kill and ultimately clear the pathogen3. J. Immunol. ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Am. Arita, M. et al. Am. FASEB J. Biochim. Tam, V. C. et al. A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation. Treatment of the host with exogenous protectin D1 can restore inhibition of viral RNA export, thereby limiting viral replication and improving host survival. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death. The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury. J. Immunol. Cyclooxygenase-2-derived prostaglandin E2 and lipoxin A4 accelerate resolution of allergic edema in Angiostrongylus costaricensis-infected rats: relationship with concurrent eosinophilia. Thoren, F. B. et al. Vaporciyan, A. Biophys. Efferocytosis also leads to further production of additional SPMs that signal for restoration of vascular integrity, regeneration and/or repair of injured tissues, remission of fever by inhibition of pro-inflammatory lipid mediators and cytokines, and relief of inflammatory pain10. Shryock, N. et al. Nat. However, some individuals exhibit insufficient levels of endogenous. As momentum grows to leverage these natural resolution pathways for rational new therapeutic strategies for diseases of acute and chronic inflammation, it is essential to clarify the roles of SPMs in human host defence and in the regulation of pathogen-mediated inflammation. Non-infectious inflammation is a common and often devastating cause of human disease. Levy, B. D. et al. T. gondii is able to generate components of SPM biosynthetic pathways, resulting in local collaboration with host cells to increase lipoxin production with the consequence of a dampened immune response to T. gondi i115. 12, 89 (2013). Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Inflamm. Haas-Stapleton, E. J. et al. V. ALTOUNIAN/SCIENCE A version of this story appeared in Science, Vol 376, Issue 6593. The disease process is thought to be mediated by an overly robust immune response to the bacteria, including to Porphyromonas gingivalis in chronic infection and Actinobacillus spp. 1). BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis. Disruption of lipoxin formation or lipoxin receptor availability delays the resolution response27,28,29,30. Immunopharmacol. Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. J. Immunol. 245, 167172 (1989). Immunol. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. Correspondence to PLoS ONE 6, e24422 (2011). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. 184, 64186426 (2010). Duffield, J. S. et al. . Prostaglandin-endoperoxide synthase genes COX1 and COX2 - novel modifiers of disease severity in cystic fibrosis patients. 3, 227233 (2015). Lymphocytes. J. Immunol. Devchand, P. R. et al. FEBS Open Bio 2, 328333 (2012). Recruitment of neutrophils, lymphocytes and eosinophils to the site of infection are all decreased by this mechanism115. J. Immunol. Physiol. By contrast, in the same model, later treatment with LXA4 had positive effects, allowing for adequate clearance of infection but dampening the protracted and pathological immune response, therefore enhancing survival97. 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. 19, 203210 (2005).
177, 59025911 (2006). Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution. Resolvin D series and protectin D1 mitigate acute kidney injury. 138, 266270 (1987). These immunoresolvents are distinct from immunosuppressive molecules as they not only dampen inflammation but also promote host defence. Resolvin E1 maintains macrophage function under cigarette smoke-induced oxidative stress. J. As discussed previously in M. tuberculosis infections, experimental models that strongly favour the generation of lipoxins over leukotrienes can have detrimental effects on pathogen clearance. Immunol. Claria, J. Of interest, protectin D1 regulates IL-5 and IL-13 but not IL-4 levels, suggesting that ILC2s rather than TH2 cells are likely to be a principal cellular target for protectin D1. J. Clin. J. Med. J. Physiol. Care Med. In addition, RvE1 enhances bacterial clearance and reduces local production of pro-inflammatory cytokines in E. coli aspiration pneumonia, which results in enhanced survival of mice13.
Roles of Specialized Pro-Resolving Lipid Mediators in - PubMed J. Pathol.
Toward a Pharmacology of Resolution | Harvard Magazine In mucosal host defence, transmigrating neutrophils initiate a respiratory burst and degranulation response to invading pathogens; however, excessive neutrophil activation can cause 'bystander' tissue damage and contribute to pathobiology of mucosal inflammatory disease75. Granulocytes in the tissue undergo apoptosis during the resolution of inflammation to prevent bystander tissue injury occurring from the release of potentially toxic cellular contents8. 164, 16631667 (2000). Nat. 205, 27912801 (2008).
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