CXCR3.1 and CXCR3.2 Differentially Contribute to Macrophage Polarization in Teleost Fish

Abstract

The study of multiple copies of chemokine receptor genes in various teleosts has long appealed to investigators seeking to understand the evolution of the immune system. The CXCR CXCR3 gene has two isoforms, CXCR3.1 and CXCR3.2, which are both expressed in macrophages. The distinct roles of teleost CXCR3s have not been identified previously. In this article, we found that CXCR3.1 and CXCR3.2 differentially contributed to macrophage polarization in the teleosts: ayu (), grass carp (), and spotted green pufferfish (). In ayu macrophages, the CXCR3.1 (PaCXCR3.1) gene was constitutively expressed, whereas the CXCR3.2 (PaCXCR3.2) gene was induced postinfection with Upon infection, PaCXCR3.1 and PaCXCR3.2 macrophages showed an M1 and an M2 phenotype, respectively. CXCL9-11-like proteins mediated M1 and M2 polarization by interacting with the PaCXCR3.1 and PaCXCR3.2 proteins on macrophages, respectively. The transcription factors STAT1 and STAT3 were activated in PaCXCR3.1 and PaCXCR3.2 macrophages, respectively. Furthermore, the prognosis of septic ayu adoptively transferred with PaCXCR3.2 macrophages was improved. Our data reveal a previously unknown mechanism for macrophage polarization, suggesting that redundant genes may regulate crucial functions in the teleost immune system.

Molecular cloning, characterization and expression analysis of MHCI and chemokines CXCR3 and CXCR4 gene from freshwater carp,Catla catla

“…31 MHCI (MG859931) sequence of C. catla showed similarity with the submitted MHCI sequence of other Cyprinidae family, similar to that of cloned CXCR3 (MK134706) and CXCR4 (MK134707) respectively. [32][33][34][35][36][37] As adaptive immunity gets triggered, various chemokines such as CXCR3, CXCR4 get secreted after the APCs link to the innate cells to regulate the signaling cascades. 38 The phylogenetic relationship of MHCI, CXCR3 and CXCR4 sequences of C. catla along with sequences of other vertebrates was computed in Mega6.0 software which showed two different clusters involving fish and mammalians.…”

“…[50][51][52][53][54][55][56][57] CXCR3 was first reported in myeloid cell development of zebra fish 58 and in medaka it was found to respond in wound healing. 22 CXCR4 gene was also characterized in rainbow trout, starlet, zebra fish and turbot 22,59,60 which proved to show its expression in regulation of immune system due to cytokine growth factors and intracellular second messengers. Such multiple roles of CXCR3 and CXCR4 in immune defense system had led to check the presence of these genes in C. catla.…”

“…The CXCR3 expressions of C. catla infected tissues irrespective of different time intervals validated with the result of other teleost fish which has been reported along with the mammalian CXCR3. [59][60][61] Lu et al 59 studied the differential contribution of CXCR3 in macrophage polarisation in teleost fish which showed that Plecoglossus altivelis with Escherichia coli infection triggered the constitutive expression in macrophages. In the present study, S. uberis infected fish showed an ubiquitous expression in all the tissues similar to various previous reports.…”

“…In the present study, S. uberis infected fish showed an ubiquitous expression in all the tissues similar to various previous reports. 55,56,59,61,62 Therefore, it can be concluded that CXCR3 maintains the homeostasis, migration and differentiation of myeloid cells. 63,64 CXCR3 also tends to have a crucial role in trafficking and migrating of activated T-cells in numerous auto-immune and inflammatory diseases.…”

Gαi2 Signaling Regulates Inflammasome Priming and Cytokine Production by Biasing Macrophage Phenotype Determination

“…FPR2 has multiple cognate ligands that drive either M1 or M2 polarization in a ligandspecific manner (12)(13)(14)(15). CXCR3 exhibits isoform restricted expression on M1 and M2 subsets, with each isoform functioning to polarize macrophages in opposite directions (16,17). ChemR23, in contrast, is only expressed on M1 macrophages and like FPR2 has multiple ligands with opposing proinflammatory/proresolving effects.…”