Les neutrophiles jouent un rôle central dans la défense de l'hôte contre les infections et les lésions tissulaires. Les neutrophiles intègrent des signaux opposés au sein du microenvironnement inflammatoire, qui convergent vers des récepteurs sélectionnés. Parmi ces récepteurs se trouve le récepteur pléiotrope, le récepteur du formyle peptide 2/récepteur de la lipoxine (FPR2/ALX) qui peut reconnaître plus de 20 ligands protéiques, peptidiques et lipidiques structurellement divers. Parmi ces ligands se trouvent des peptides N-formylés libérés par les mitochondries de cellules hôtes mourantes ou mortes. À l'heure actuelle, on sait peu de choses sur la base moléculaire de la façon dont FPR2/ALX intègre des signaux opposés et déclenche diverses réponses biologiques. Nous avons constaté que le récepteur pléiotrope FPR2/ALX intègre des signaux opposés qui régissent la phagocytose, la destruction bactérienne, le sort des neutrophiles et, finalement, le résultat de la réponse inflammatoire. Cette action des peptides N-formylés est médiée par l'induction de la libération d'élastase neutrophile à partir des granules primaires et la régulation négative subséquente du récepteur C5a du complément à la surface cellulaire, qui peut être inversée par des médiateurs lipidiques pro-résolvants, déclenchée par l'aspirine 15-épi- lipoxine A4 (15-epi-LXA4) et 17-épi-résolvine D1 (17-epi-RvD1). Cela peut contribuer au développement de nouvelles stratégies pharmacologiques visant à améliorer les mécanismes de protection médiés par FPR2/ALX qui peuvent limiter la réponse inflammatoire et favoriser la résolution de l'inflammation. / Neutrophils play a central role in host defense against infection and tissue injury. PMNs integrate opposing cues within the inflammatory microenvironment, which converge on selected receptors. Among these receptors is the pleiotropic receptor, formyl peptide receptor 2/lipoxin receptor (FPR2/ALX), which can recognize over 20 structurally diverse proteins, peptides, and lipid ligands. Among these ligands are N-formylated peptides released from mitochondria of dying or dead host cells. At present, little is known about the molecular basis for how FPR2/ALX integrates opposing cues and triggers diverse biological responses. We wanted to test the effect of N-formylated peptides on human neutrophils' functions in sepsis-like syndrome. We found that the pleiotropic receptor FPR2/ALX integrates opposing signals that govern phagocytosis, bacterial killing, the fate of neutrophils, and ultimately the outcome of the inflammatory response. This action of N-formylated peptides is mediated through induction of the release of neutrophil elastase from the primary granules and subsequent downregulation of complement C5a receptor on the cell surface. This effect can be reversed by pro-resolving lipid mediators, aspirin-triggered 15-epi-lipoxin A4 (15-epi-LXA4) and 17-epi-resolvin D1 (17-epi-RvD1). Our results could lead to the development of novel pharmacological strategies to enhance FPR2/ALX-mediated protective mechanisms that may limit the inflammatory response and promote the resolution of inflammation.

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Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far. Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry. Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion. Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.