V-domain Ig suppressor of T-cell Activation (VISTA): Bone Marrow Derived Macrophage Reprogramming as Treatment for Immune Dysfunction 2335044

Abstract

Abstract Introduction Acute respiratory distress syndrome (ARDS) is characterized by dysregulated inflammation leading to increased microvascular permeability, pulmonary edema, and organ failure. ARDS commonly complicates septic patients, and accounts for 10% of intensive care unit admissions with a 35-45% mortality and no effective pathological-pharmacological treatment available. Bone marrow-derived macrophages (BMDMs) contribute to pulmonary damage in ARDS by adopting a pro-inflammatory phenotype and producing inflammatory mediators in the lung tissue. V-domain Ig Suppressor of T-cell Activation (VISTA), a negative checkpoint regulator expressed across the hematopoietic compartment, has been shown to promote an anti-inflammatory phenotype in macrophages and maintain a protective effect on survival in response to both septic and ARDS challenge. Methods Using an indirect ‘double hit’ ARDS mouse model of fixed pressure hemorrhagic shock (Hem) followed by a polymicrobial sepsis insult through the cecal ligation and puncture (CLP) procedure, we examined VISTA function in BMDMs from wild-type (WT) and VISTA deficient (VISTAKO) mice. Bone marrow samples were harvested from Hem/CLP challenged mice and BMDMs were cultured and polarized in-vitro for characterization through flow cytometry analysis and functional assays. Results Early data shows that VISTA KO BMDMs exhibit higher pro-inflammatory markers and MHCII expression in both Hem/CLP and sham control mice compared to WT macrophages. Lastly, VISTA KO Hem/CLP BMDMs exhibit higher production of inflammatory cytokines such as IL-6 and TNF-α even when polarized with IL-4 compared to Hem/CLP WT macrophages. Conclusion Our results highlight the role of VISTA function in BMDMs in the development of pulmonary damage seen during ARDS. Future studies will analyze how anti-inflammatory cytokine production is affected by VISTA and if VISTA agonistic treatment can alleviate increased proinflammatory function exhibited by BMDMs during ARDS. Funding Source R35 GM118097 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)