Macrophage ACKRobatics: An atypical Cxcr3 keeps macrophages in check
| Autor: | Gopinath Viswanathan, David M. Tobin |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
animal structures Receptors CXCR3 Immunology chemical and pharmacologic phenomena CXCR3 Infections 03 medical and health sciences 0302 clinical medicine GPCR stomatognathic system immune system diseases Cell Movement Immunology and Allergy Macrophage Animals paralogs Receptor Zebrafish scavenger ACKR biology Extramural Macrophages fungi hemic and immune systems Cell Biology Cell movement biology.organism_classification Cell biology stomatognathic diseases 030104 developmental biology Highlighted Article motility 030220 oncology & carcinogenesis Mycobacterium marinum Spotlight on Leading Edge Research |
| Zdroj: | Journal of Leukocyte Biology |
| ISSN: | 1938-3673 |
| Popis: | The CXCR3‐CXCL11 chemokine‐signaling axis plays an essential role in infection and inflammation by orchestrating leukocyte trafficking in human and animal models, including zebrafish. Atypical chemokine receptors (ACKRs) play a fundamental regulatory function in signaling networks by shaping chemokine gradients through their ligand scavenging function, while being unable to signal in the classic G‐protein‐dependent manner. Two copies of the CXCR3 gene in zebrafish, cxcr3.2 and cxcr3.3, are expressed on macrophages and share a highly conserved ligand‐binding site. However, Cxcr3.3 has structural characteristics of ACKRs indicative of a ligand‐scavenging role. In contrast, we previously showed that Cxcr3.2 is an active CXCR3 receptor because it is required for macrophage motility and recruitment to sites of mycobacterial infection. In this study, we generated a cxcr3.3 CRISPR‐mutant to functionally dissect the antagonistic interplay among the cxcr3 paralogs in the immune response. We observed that cxcr3.3 mutants are more susceptible to mycobacterial infection, whereas cxcr3.2 mutants are more resistant. Furthermore, macrophages in the cxcr3.3 mutant are more motile, show higher activation status, and are recruited more efficiently to sites of infection or injury. Our results suggest that Cxcr3.3 is an ACKR that regulates the activity of Cxcr3.2 by scavenging common ligands and that silencing the scavenging function of Cxcr3.3 results in an exacerbated Cxcr3.2 signaling. In human, splice variants of CXCR3 have antagonistic functions and CXCR3 ligands also interact with ACKRs. Therefore, in zebrafish, an analogous regulatory mechanism appears to have evolved after the cxcr3 gene duplication event, through diversification of conventional and atypical receptor variants. CXCR3 paralog with structural characteristics of atypical chemokine receptors regulates the activity of a conventional receptor involved in macrophage motility by scavenging shared ligands. |
| Databáze: | OpenAIRE |
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