Paired Immunoglobulin-Like Receptors Impact The Differentiation of Reparative Macrophages Following Allogeneic Challenge

Résumé fourni par la source

Abstract Monocytes differentiate into CD206+ CD301+ reparative macrophages (MΦs) that orchestrate tissue repair in response to damage signals and cytokines. Yet, transplanting allogeneic materials produces a novel situation where innate allorecognition of mismatched MHCI may disrupt normal MΦ responses. B6 monocyte paired immunoglobulin-like receptor (PIR)-A3 recognizes BALB/c H2-Dd to generate pro-inflammatory dendritic cells that promote kidney and heart transplant rejection. Conversely, monocyte PIR-B binding to self MHCI negatively regulates PIR-A signals. How PIRs shape MΦ differentiation after Tx was not understood, so we tested the hypothesis that recognition of self-versus-allogeneic MHCI by PIRs divergently modulates MΦ differentiation. Monocyte-derived MΦ differentiation in wild type (WT), Rag2−/− γc−/−, Pira−/− and Pirb−/− B6 mice was assessed by flow cytometry 3 days after exposure to 20×106 radiation-damaged BALB/c allogeneic (allo) or B6 syngeneic (syn) splenocytes administered intraperitoneally. Syn materials predominantly stimulated monocyte differentiation into phenotypically reparative MΦs. Allo cells instead transformed monocytes exclusively into pro-inflammatory Ly6chi CD86hi MΦs. Rag2−/− γc−/− mice behaved similarly. IL-33 released from injured cells metabolically reprograms infiltrating monocytes and MΦs to support their differentiation into CD206+ CD301+ MΦs. Interestingly, Pirb−/− mice display greatly reduced C206+ CD301+ MΦs, which correlated with their decreased expression of the IL-33 receptor. Our data provide important insights into how innate allorecognition by PIR-A disrupts the typical generation of reparative MΦs in response to injured self that is supported by PIR-B. Supported by 5T32AI074490-14

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.