Modulation of innate immune exhaustion during sepsis

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PROJECT SUMMARY Existing approaches targeting selected pro- or anti-inflammatory mediators during experimental sepsis mostly ended in failure, due to the un-resolved predicament of sepsis patients experiencing the dichotomy of severe immune-suppression as well as exacerbated pathogenic inflammation, collectively contributing to increased multi-organ injuries and compromised immune defense toward secondary infections. Our integrated experimental and computational studies combined with scRNAseq analyses expanded our understanding of the traditionally defined immature Ly6Chi myeloid derived suppressor cells (MDSCs) seen in human and animal sepsis, in that these less-differentiated Ly6Chi monocytes are not only immune suppressive (with elevated immune suppressor PD-L1 and reduced immune activator CD86), but also highly pathogenic inflammatory (with sustained ROS, and elevated inflammatory mediators S100A8/9, CD38 and CX43), characteristic of septic monocytes from human patients and animals with experimental sepsis. Instead of the traditional narrow definition of MDSC partially emphasizing their immune-suppressive features, we propose the holistic concept of “exhausted memory monocytes” encompassing both immune suppression and pathogenic inflammation. Mechanistically, we recently reported that the less-studied TLR4 adaptor molecule TRAM is critically involved in the generation of exhausted monocytes, and that TRAM deletion can alleviate experimental sepsis. Based on these novel findings, our long-term goal is to define novel therapeutic targets for relieving innate immune exhaustion and preventing/treating sepsis. As a crucial first step, our key objective is to better characterize the generation of “memory” exhausted monocytes and key underlying mechanisms. We plan to test the central hypothesis that the generation of monocyte exhaustion memory during sepsis pathogenesis are mediated by the novel TRAM signaling circuitry, and that targeting TRAM will hold a therapeutic potential in restoring monocyte homeostasis and preventing/treating severe sepsis. To test this hypothesis, we plan to perform the following integrated studies. Aim 1. To test the novel phenotypic hypothesis that TRAM mediates the generation of memory exhausted monocytes during sepsis. Aim 2. To characterize novel mechanisms underlying TRAM-mediated generation of exhausted monocytes. Aim 3. To examine the translational potential of sepsis intervention via reprogramming exhausted monocytes. Completion of this project will holistically reveal important and novel mechanisms responsible for the generation of monocyte exhaustion memory leading to sepsis pathogenesis, and facilitate the development of effective therapeutic strategies in restoring monocyte homeostasis and reducing sepsis mortality/morbidity.