The immunoreceptor CD300a controls the intensity of inflammation and dysfunction in a model of Ag-induced arthritis in mice

Abstract

CD300a is an inhibitory immunoreceptor expressed in lymphoid and myeloid cells. This study evaluates whether CD300a plays a role in the control of joint inflammation in a model of Aginduced arthritis (AIA) in mice. CD300a was found to be expressed mostly on neutrophils and its expression was enhanced on neutrophils that migrated to the inflamed synovial cavity. Joint inflammation, as characterized by neutrophil accumulation, was significantly greater in CD300a KO (CD300a −/− ) mice subjected to AIA, as compared to WT mice. This was associated with joint dysfunction, as measured by lower mechanical nociception threshold. There was greater production of the chemokine CXCL1 and the cytokine IL-6 in joints of CD300a −/− mice. In vitro, M s from CD300a −/− mice released higher concentrations of CXCL1 and IL-6 in response to LPS. Splenocytes from immunized CD300a −/− mice produced increased levels of IFN-and IL-17 and lower levels of IL-10 when challenged with Ag than cells from WT mice. Neutrophils lacking the CD300a gene had greater chemotactic activity in response to fMLP, CXCL1, and LTB4 than WT neutrophils.In conclusion, these results reveal that the absence of CD300a promotes exacerbation of inflammation in a model of Ag-induced arthritis, suggesting that CD300a is an important receptor for negatively controlling the inflammatory response in this model. Mechanistically, CD300a seems to regulate the activity of various immune cells types involved in the process, including neutrophils, M s, and lymphocytes. K E Y W O R D S joint inflammation, neutrophils, pain, cytokines, CD300a, inflammation, arthritis, regulation, mice of the ITIM are phosphorylated by Src kinases and serve as a docking point for phosphatases containing the src-homology 2 (SH2) domain. 8 Proteins containing consensus sequences for interaction with phosphorylated ITIMs include the SH2 domain-containing tyrosine phosphatase (SHP)-1, SHP-2, and the SH2 domain-containing inositol 5 ′ -phosphatase. 6 The recruitment of phosphatases to the J Leukoc Biol. 2019;106:957-966.

IL-34 Actions on FOXP3+ Tregs and CD14+ Monocytes Control Human Graft Rejection

“…Further analysis of significant genes differentially expressed between IL-34 and CSF-1-macrophages revealed differential expression of 61 genes, with an upregulation of the expression of some interesting genes. Among those genes, we identified PDK4, a metabolic checkpoint for macrophage differentiation, CHI3L1, a carbohydrate-binding lectin that may play a role in tissue remodeling and cell capacity to respond to the environment involved in regulating Th2 cell responses and M2 macrophages differentiation, FCER1A, a receptor expressed by DCs that can play pro-or anti-inflammatory roles, and CD300A, a cell membrane receptor that contains classical ITIM motifs and negatively regulates Toll-like receptor (TLR) signaling mediated by MYD88 through the activation of PTPN6 and of macrophages in animal models (21). In contrast, we observed a down-regulation of MARCO, a marker of pro-inflammatory macrophages in IL-34-differentiated macrophages compared to CSF-1-differentiated macrophages ( Figure 3E and Supplementary Figure 2C).…”

Transcriptomic signature and metabolic programming of bovine classical and nonclassical monocytes indicate distinct functional specializations

“…Other anti-inflammatory genes over-expressed by ncM and intM are reported to be mostly involved in negative regulation of NF-κB signaling ( NUMBL , TNIP3 , TRIB3 (77), ZCCHC11 , DYNC2I2 (78), ZFAND6 (79), MTURN (80), HIVEP3 (81), DUSP5 , LRRC25 , COMMD9 (82), ADCY7 (83)), but also include surface receptors involved in regulation of inflammation, such the receptor of resolvin D2 ( GPR18 ) (84), SLAMF7 (85), SUCNR 1 (86), and CD300A (87).…”

CD300a contributes to the resolution of articular inflammation triggered by MSU crystals by controlling neutrophil apoptosis

“…Current studies on resolution of inflammation aim to find ways to restore tissue homeostasis by using pro-resolving mediators and, more recently, by studying mechanisms involving inhibitory receptors [19,[34][35][36]. CD300a is an increasingly studied inhibitory receptor that is shown to have an anti-inflammatory role in the context of several models of inflammatory disease, including antigen-induced arthritis [11], atopic dermatitis [19] and allergic models [18,37]. CD300a has been demonstrated to be important to limit the function of eosinophils, basophils and mast cells [19,38], but much less is known about the importance of CD300a on neutrophils, one of the most important leucocytes in the process of inflammation and resolution of inflammation [17,39].…”

“…A blood sample was collected from healthy volunteer donors (Ethics Committee on Human Research of Universidade Federal de Minas Gerais (COEP/UFMG protocol no. 0319.0.203.000-11)) in tubes with EDTA-containing Vacuette ® system (3•2%), and neutrophils were isolated through double-density gradient using Histopaque ® 10 771 and 11 191 (Sigma-Aldrich, St. Louis, MO, USA) as previously described [11]. Neutrophils were incubated at 37° and 5% CO 2 with or without mouse anti-human CD300a (Hybridoma #12, produced in-house, Jerusalem) agonistic antibody for 5 and 15 min and for 8 hr, to perform Western blot analysis and flow cytometry analysis, respectively.…”

“…CD300a is present in myeloid and lymphoid cells of humans and mice [8]. Studies on CD300a demonstrate its capacity to modulate cell activation, cytokine production and cell migration [9][10][11]. CD300a was first described in 1999, and relatively little knowledge about it exists to date in several pathologies, which makes its study important [12].…”