Novel mechanisms for the generation of resolving monocytes

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PROJECT SUMMARY Low-grade inflammatory monocytes are increasingly recognized as key contributors for the pathogenesis of atherosclerosis through their enhanced recruitment and retention within the atherosclerotic plaques, as well as their compromised ability of cleaning up necrotic cell debris. However, mechanisms responsible for resolving monocyte inflammation are poorly understood, thus hindering translational efforts in resolving monocyte- mediated inflammatory polarization and the treatment of atherosclerosis. The PI recently reported that the training of low-grade inflammatory monocytes requires the critical cellular TLR4 adaptor molecule TRAM. Our data show that TRAM is uniquely responsible for the inflammatory polarization of monocytes, through a novel mechanism in disrupting pexophagy-mediated peroxisome homeostasis. Tram-/- monocytes have elevated PPAR and PEX5, enhanced pexophagy, reduced ROS, and reduced inflammatory polarization. Intriguingly, Tram-/- monocytes also express increased anti-inflammatory mediators (RvD1 and CD200R) characteristic of “resolving” monocytes, and can actively propagate resolution to neighboring monocytes through CD200R in vitro and in vivo. Tram-/- mice exhibit reduced development of atherosclerosis. Transfusion of Tram-/- resolving monocytes can reduce atherosclerosis pathogenesis. Based on these novel findings, the long term goal is to define novel therapeutic targets for sustaining monocyte homeostasis and preventing/treating atherosclerosis. The current objective is to define molecular and cellular mechanisms by which TRAM may serve as a key switch controlling the generation of either inflammatory or resolving monocytes relevant to the pathogenesis or treatment of atherosclerosis. The central hypothesis is that TRAM deletion will not only block the polarization of low-grade inflammatory monocytes, but also enable the generation and propagation of resolving monocytes conducive for the treatment of atherosclerosis, through enhancing peroxisome homeostasis. To test this hypothesis, the following integrated studies will be conducted. Aim 1 will test the hypothesis that the TRAM- PSMB10 circuitry drives the inflammatory polarization of low-grade inflammatory monocytes through disrupting pexophagy. Aim 2 will test the hypothesis that TRAM deletion and reduction of immunoproteasome PSMB10 enable the generation of anti-inflammatory resolving monocytes through sustained activation of PPAR /peroxisome homeostasis. Aim 3 will test the translational hypothesis that resolving monocytes with enhanced peroxisome homeostasis can propagate resolution memory and reduce the pathogenesis of atherosclerosis. Together, the proposed studies will advance the field of innate immune memory, by delineating the novel role of TRAM-circuitry in the training of “inflammatory” vs “resolving” monocytes, bearing translational relevance to the pathogenesis and treatment of atherosclerosis.