Infection-induced cell cycle diversion promotes macrophage inflammatory biogenesis

About This Grant

Infection-induced cell cycle diversion promotes macrophage inflammatory biogenesis Project Summary Infection of macrophages by bacterial pathogens triggers a profound structural and biochemical remodeling process that drives the inflammatory response. A productive macrophage inflammatory response is characterized by altered mitochondrial metabolism and increased cytokine secretion, yet the mechanisms that reshape cellular infrastructure to support these key functions are not well understood. Studies from our laboratory and others clearly demonstrate that mitochondrial morphology, metabolism and signaling are central to host defense and inflammation. Our preliminary data show that macrophage infection by the bacterial pathogen methicillin-resistant Staphylococcus aureus (MRSA) stimulates mitochondrial biogenesis, without concomitant DNA synthesis or cell division. Using a chemogenomics approach to probe the connections between mitochondrial form and function, we find that inhibition of specific cell cycle regulators in infected macrophages prevents organelle biogenesis and limits production of inflammatory cytokines, despite the lack of cell division. Indeed, MRSA induction of mitochondrial biogenesis in primary or immortalized macrophages appears comparable to compounds that induce mitotic blockade. Notably, infection-induced mitochondrial biogenesis appears to be refractory to perturbation of canonical regulators of biogenesis such as PGC-1α. Together, these observations lead to our central hypothesis that macrophage sensing of bacterial infection initiates a specialized inflammatory biogenesis program by stimulating entry of macrophages into G1 for organelle expansion, while blocking commitment to S phase to prevent DNA synthesis during this period of acute oxidative stress. We reason that organelle expansion supports acute metabolic remodeling and cytokine secretion, and blocking S phase entry prevents partitioning of newly expanded cellular infrastructure and protects genome fidelity by limiting synthesis during the oxidative stress associated with robust host defense. We will test this hypothesis by (1) identifying the critical regulatory steps that distinguish the canonical cell cycle from inflammatory biogenesis, and (2) defining how inflammatory mitochondrial biogenesis differs from the canonical biogenesis program to enable host defense and inflammation. These studies will yield mechanistic insight into the blueprint for macrophage innate immune defense and elucidate therapeutic opportunities to modulate inflammation and infection.