Saturated‐efferocytosis generates pro‐resolving CD11b low macrophages: Modulation by resolvins and glucocorticoids

Proteinase 3 (PR3) is the target of anti-neutrophil cytoplasm Abs in granulomatosis with polyangiitis, a form of systemic vasculitis. Upon neutrophil apoptosis, PR3 is coexternalized with phosphatidylserine and impaired macrophage phagocytosis. Calreticulin (CRT), a protein involved in apoptotic cell recognition, was found to be a new PR3 partner coexpressed with PR3 on the neutrophil plasma membrane during apoptosis, but not after degranulation. The association between PR3 and CRT was demonstrated in neutrophils by confocal microscopy and coimmunoprecipitation. Evidence for a direct interaction between PR3 and the globular domain of CRT, but not with its P domain, was provided by surface plasmon resonance spectroscopy. Phagocytosis of apoptotic neutrophils from healthy donors was decreased after blocking lipoprotein receptor-related protein (LRP), a CRT receptor on macrophages. In contrast, neutrophils from patients with granulomatosis with polyangiitis expressing high membrane PR3 levels showed a lower rate of phagocytosis than those from healthy controls not affected by anti-LRP, suggesting that the LRP-CRT pathway was disturbed by PR3-CRT association. Moreover, phagocytosis of apoptotic PR3-expressing cells potentiated proinflammatory cytokine in vitro by human monocyte-derived macrophages and in vivo by resident murine peritoneal macrophages, and diverted the anti-inflammatory response triggered by the phagocytosis of apoptotic cells after LPS challenge in thioglycolate-elicited murine macrophages. Therefore, membrane PR3 expressed on apoptotic neutrophils might amplify inflammation and promote autoimmunity by affecting the anti-inflammatory “reprogramming” of macrophages.

Section: Phagocytosis Of Apoptotic Pr3-expressing Cells Induced a Promentioning

confidence: 86%

Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation

Gabillet

Millet

Pederzoli-Ribeil

et al. 2012

“…A transcriptomic analysis showed that resolution phase macrophages transcribe high levels of IL-10, COX-2, and of the mannose receptor, and despite the low secretion, also high levels of inflammatory cytokines (53). In the same mouse model, peritoneal injection of RvE1 induced the formation of CD11b low macrophages with high phagocytic capacity, reduced TNF-a, and increased IL-10 secretion reflecting the proresolution effect of RvE1 in mouse macrophages (54). Although some characteristics of the resolution phase mouse macrophages described in the earlier mentioned studies differ from the characteristics of the RvE1 restimulated M1 human macrophages in our in vitro experiments, we also observed an increased IL-10 expression and an increased phagocytic capacity after RvE1 treatment, suggesting that RvE1 does repolarize human primary M1 macrophages toward a resolution phase macrophage.…”

Section: Discussionmentioning

confidence: 97%

ChemR23, the Receptor for Chemerin and Resolvin E1, Is Expressed and Functional on M1 but Not on M2 Macrophages

Herová

Schmid

Gemperle

et al. 2015

133

100

ChemR23 is a G protein–coupled receptor that is triggered by two ligands, the peptide chemerin and the eicosapentaenoic acid–derived lipid mediator resolvin E1 (RvE1). Chemerin acts as a chemoattractant for monocytes and macrophages, whereas RvE1 promotes resolution of inflammation-inducing macrophage phagocytosis of apoptotic neutrophils. Although ChemR23-mediated signaling plays a role in mononuclear cell migration to inflamed tissue, as well as in the resolution of inflammation, its regulation in different polarization states of macrophages is largely unknown. We analyzed the expression and function of ChemR23 in monocytes and differently activated human primary macrophages. Using 5′ RACE, we identified three transcription start sites and several splice variants of ChemR23 in both monocytes and macrophages. Although the promoters P1 and P3 are used equally in unpolarized macrophages, stimulation with LPS or IFN-γ leads to increased transcription from P3 in inflammatory M1 macrophages. Such ChemR23-expressing M1 macrophages are chemotactic to chemerin, whereas M2 macrophages not expressing ChemR23 surface receptor are not. Repolarization of ChemR23-expressing M1 macrophages with 10 nM RvE1 increases IL-10 transcription and phagocytosis of microbial particles, leading to a resolution-type macrophage distinct from the M2 phenotype. These results show that ChemR23 is tightly regulated in response to inflammatory and anti-inflammatory stimuli. The restricted expression of ChemR23 in naive and M1 macrophages supports the role of ChemR23 in the attraction of macrophages to inflamed tissue by chemerin and in the initiation of resolution of inflammation through RvE1-mediated repolarization of human M1 macrophages toward resolution-type macrophages.

“…Such mediators have the potential to inhibit further PMN recruitment, intensify monocyte migration, and amplify efferocytosis. M2 macrophages then switch to Mres phenotype, which display reduced phagocytosis, but instead produce antifibrotic and antioxidant proteins that limit tissue damage and fibrosis (28). It has been demonstrated that GILZ is constitutively expressed in nonphlogistic conditions in human and murine macrophages (39).…”

Section: Discussionmentioning

confidence: 99%

“…In the early phase of inflammation macrophages are an important source of cytokines and inflammatory mediators, but at later time points this cell type is crucial for the resolution of inflammatory response (27). Based on a recent description of three macrophage populations, that is, M1 (F4/80 low Gr1 + Cd11b med ), M2 (F4/80 high Gr1 2 Cd11b high ), and Mres (F4/80 med Cd11b low ) (28,29), we performed evaluation of these populations by flow cytometry in cells from the pleural cavity of LPS-injected mice. As shown in Fig.…”

Section: Self-resolving Inflammation Of Lps-induced Pleurisy Is Accommentioning

confidence: 99%

The Role and Effects of Glucocorticoid-Induced Leucine Zipper in the Context of Inflammation Resolution

Vago

Tavares

Garcia

et al. 2015

108

Glucocorticoid (GC)-induced leucine zipper (GILZ) has been shown to mediate or mimic several actions of GC. This study assessed the role of GILZ in self-resolving and GC-induced resolution of neutrophilic inflammation induced by LPS in mice. GILZ expression was increased during the resolution phase of LPS-induced pleurisy, especially in macrophages with resolving phenotypes. Pretreating LPS-injected mice with trans-activator of transcription peptide (TAT)–GILZ, a cell-permeable GILZ fusion protein, shortened resolution intervals and improved resolution indices. Therapeutic administration of TAT-GILZ induced inflammation resolution, decreased cytokine levels, and promoted caspase-dependent neutrophil apoptosis. TAT-GILZ also modulated the activation of the survival-controlling proteins ERK1/2, NF-κB and Mcl-1. GILZ deficiency was associated with an early increase of annexin A1 (AnxA1) and did not modify the course of neutrophil influx induced by LPS. Dexamethasone treatment resolved inflammation and induced GILZ expression that was dependent on AnxA1. Dexamethasone-induced resolution was not altered in GILZ−/− mice due to compensatory expression and action of AnxA1. Our results show that therapeutic administration of GILZ efficiently induces a proapoptotic program that promotes resolution of neutrophilic inflammation induced by LPS. Alternatively, a lack of endogenous GILZ during the resolution of inflammation is compensated by AnxA1 overexpression.