Project Summary Sepsis is a life-threatening disease caused by dysregulated host responses to infection. Sepsis remains a major health problem worldwide with high mortality. Myeloid cell responses such as endotoxin tolerance, epigenetic modification, metabolic failure, and apoptosis are profoundly affected in sepsis, which leads to systemic dysfunction of immune cells and progenitor cells. The regulation of myeloid cell responses in sepsis remains largely unknown. The histone deacetylase HDAC6 regulates a variety of cellular responses. However, HDAC6 regulation of myeloid cell responses in sepsis has not been investigated. Our preliminary studies indicate that HDAC6 is a key mediator of cell signaling in myeloid cells. Myeloid-specific HDAC6 deletion reduces the mortality in septic mice. Furthermore, selective HDAC6 inhibition can modulate myeloid cell responses in the mouse models of sepsis. In the proposed studies, we will test the hypothesis that HDAC6 activation mediates myeloid cell dysfunction in sepsis, and HDAC6 inhibition could improve myeloid cell function and survival rate in sepsis.