TIM-3- and TIM-4-mediated phagocytosis of apoptotic cells induces cytokine production in peritoneal macrophages (100.55)

Abstract TIM-3 and TIM-4 mediate phagocytosis of apoptotic cells by recognizing phosphatidylserine on the surface of the apoptotic cell but are expressed by different cell populations, suggesting each has distinct functions in regulating immune responses. TIM-4 is exclusively expressed on APCs while TIM-3 is expressed on some T cell and APC subsets. We found that TIM-4 was constitutively expressed on mouse resident peritoneal macrophages (PMϕ) and played a predominant role in phagocytosis of apoptotic cells. Following phagocytosis of apoptotic cells, PMϕ secreted CCL2 (MCP-1), CCL3 (MIP-1 α), CCL4 (MIP-1β), CCL7 (MCP-3), CCL9 (MIP-1γ), CXCL-2 (MIP-2), CCL19 (MIP-3), CCL22 (MDC), IL-10 and TGF-β. mRNA levels of these cytokines increased very early (peaking at 0.5-4 hours), but the peak of protein level occurred 48-72 hours after phagocytosis. When TIM-4 on PMϕ was blocked by TIM-4 antibody, phagocytic activity was dramatically decreased and cytokine expression reduced. Following in vivo thioglycollate treatment, expression of TIM-4 by PMϕ was gradually lost, whereas expression of TIM-3 increased. TIM-3-mediated phagocytosis by thioglycollate-induced PMϕ resulted in a generally similar cytokine production pattern compared with TIM-4 mediated phagocytosis by PMϕ, but also resulted in the production of IL-1β and TNF-α. In summary, both TIM-4 and TIM-3 mediated phagocytosis of apoptotic cells and promoted macrophage production of cytokines that further regulates the immune response.