VISTA Regulates Proinflammatory Function by Tissue Resident Peritoneal Macrophages in Response to Hemorrhagic Shock and Septic Challenge 2310024

Abstract Introduction Traumatic injury, like hemorrhagic shock, serves as an immune predisposition ‘priming’ event, where upon a secondary challenge a heightened inflammatory response can occur, culminating in clinical complications such as septic multiple organ failure. Large (LPM) and small (SPM) peritoneal tissue resident macrophages play a significant role in peritoneal homeostatic functions and in initiating the local immune response upon injury/infection. V-domain Ig suppressor of T-cell Activation (VISTA) has a protective effect in response to shock and septic challenge able to suppress T-cell effector function and promoting an anti-inflammatory phenotype in monocyte-derived macrophages (Mo-Macs). However, VISTA function in tissue resident peritoneal macrophages in response to shock and sepsis has yet to be studied. Methods Using a ‘double hit’ shock and sepsis induced multiple organ injury mouse model, consisting of fixed pressure hemorrhagic shock (Hem) insult followed by sepsis through the cecal ligation & puncture (CLP) method, the effects of VISTA function on the immune contribution by resident peritoneal macrophages was characterized through flow cytometry. Results Our initial data shows that following Hem/CLP, VISTA expression is upregulated in LPMs but remains constant in SPMs and Mo-Macs. However, both LPMs and SPMs are significantly depleted from the peritoneum after Hem/CLP challenge. Lastly, pro-inflammatory markers are increased in SPMs and Mo-Macs, and VISTA deficiency leads to downregulation of MHCII expression in SPMs. Conclusion These results indicate that VISTA regulates the inflammatory SPM population through its constitutive expression in peritoneal macrophages as a mechanism that promotes an anti-inflammatory phenotype and through VISTA and MHCII mediated interaction with T cells. VISTA plays a novel role as a negative regulator of innate inflammation following shock and septic insult by regulating macrophage mediated inflammation through the activation of anti-inflammatory pathways. Funding Source R35 GM118097 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)