Tim4 regulates NALP3 inflammasome expression and activity during monocyte/macrophage dysfunction in septic shock patients.

Sepsis is the leading cause of death in burn patients. Monocytes/macrophages rapidly exhibit impaired production of proinflammatory cytokines and an elevated generation of anti-inflammatory cytokines in septic patients with immunosuppression. However, the expression patterns of Tim4 and Nod-like receptor protein 3 (NALP3) inflammasome and their roles during immunosuppression in septic shock patients are not well understood. Tim4 and NALP3 inflammasome expression in monocytes were downregulated in immunosuppressive patients with sepsis compared with healthy volunteers. Meanwhile, NALP3 inflammasome expression was upregulated by Tim4 overexpression in murine bone marrow-derived macrophages (BMDMs) and J774A.1 macrophages. Tim4 overexpression improved the ability of BMDMs and J774A.1 macrophages to produce proinflammatory cytokines and increased the expression of cleaved-caspase-1 (p10) after LPS/ATP stimulation. In addition, overexpression of Tim4 enhanced phagocytosis of apoptotic polymorphonuclear neutrophils (PMNs) by BMDMs and J774A.1 macrophages, while depletion of NALP3 in Tim4 overexpressing BMDMs and J774A.1 macrophages decreased phagocytosis of apoptotic PMNs. In summary, the expression of Tim4 and NALP3 inflammasome in monocytes/macrophages was downregulated in septic shock patients, and diminished expression of Tim4 and NALP3 inflammasome in monocytes/macrophages might play a critical role in sepsis-elicited immunosuppression.