Macrophage recognition of non-self MHCI triggers signaling pathways directing differentiation and initiating tissue repair.

Abstract Injury resolution requires a coordinated immune-mediated response executed by macrophages (MΦs). Yet, how MΦs convert local stimuli into effective repair is poorly understood. Furthermore, organ transplants (Tx) will fail over time due to fibrosis, despite immunosuppressants targeting adaptive immune cells. We hypothesizethis dysregulated MΦ-mediated tissue of grafts. Donor MHCI can be recognized monocytes and via paired-immunoglobulin-like receptor-A (PIR-A), but if non-self recognition disrupts an unanswered question. To test this, Wildtype (WT), Rag2 −/−γc −/−, Pira −/−C57BL/6 (H-2 b) MΦ differentiation was assessed after exposure allogeneic (BALB/c; H-2 d; allo) or syngeneic (syn) materials using flow cytometry phosphoflow. The function syn- allo-exposed were compared with live-cell imaging wound healing assays. Allo generated Ly6c hiCD86 hiMΦs in both WT −/−recipients vivo. Recombinant H2-D dalone behaved similarly vitro. Interestingly, hiMΦ not PIR-A mediated, Ly49d-triggered PLCγ2 activation NF-κB mTOR coupled increased glycolysis. Moreover, allo profoundly amplified comparison other well characterized subsets (i.e. LPS/IFNγ IL-4 stimulated). identify unappreciated relationship between innate allorecognition repair. Specifically, recognize Ly49d, triggering this novel pathway mediates phenotypically pro-inflammatory functions. Such mechanism would contribute Tx graft fibrosis related pathology time. Supported grants from NIH (5T32AI074490-14, R01HL122489)