Overproduction of proinflammatory cytokines by macrophages and other cells is critical in the development of septic shock. On the other hand, immunocompromise of macrophages and lymphocytes that developed during the onset of sepsis was also believed to contribute to the lethality of this disease. The lifespan of macrophages and lymphocytes was modulated in sepsis and is responsible, in part, for the uncontrolled inflammatory response and immunodepression. Recent studies have shown that inhibition of lymphocyte apoptosis increased the survival rate of sepsis in an animal model. However, the effect of macrophage apoptosis on the outcome of sepsis has not been addressed. We found that macrophage apoptosis was induced in the same animal model when caspase inhibitor was administered to prevent lymphocyte death. We also found that Nur77 was induced in apoptotic macrophages and Nur77 induction is required for macrophage death. As reported by others using other types of cells, Nur77 induction requires transactivation of MEF2, but a signaling triggered by bacterial components is also required for macrophage expression of Nur77. This proposal will use the knowledge we have of macrophage apoptosis to promote and inhibit macrophage death in septic mice and thereby determine whether macrophage apoptosis positively or negatively affects the outcome in septic mice. We will also further elucidate the molecular mechanisms underlying the macrophage apoptosis. The proposed study will provide information regarding whether macrophage death should be avoided or enhanced in the treatment of sepsis. Our study will also lead to a better understanding of how macrophage apoptosis is controlled, which is needed to develop therapeutically useful strategies to selectively promote or inhibit macrophage death.
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