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Profiling the role of conventional type 1 dendritic cells during sterile inflammation

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Conventional type 1 dendritic cells (cDC1s) act as sentinels of the immune system, surveying the surrounding environment to integrate, process, and present signals in order to initiate inflammatory responses. In concert with additional tissue-resident innate lymphocyte populations including type 1 innate lymphoid cells (ILC1s), these subsets initiate and potentiate inflammation early during infection to restrict pathogen expansion. However, the role that cDC1s and ILC1s play during “sterile” pathogen-less inflammation is less well understood. As sterile inflammation is activated during wound healing, trauma, drug-induced injury, obesity, and anti-tumor responses, understanding the mechanisms that drive sterile inflammation is critical to the development of therapeutic strategies aimed at improving multiple disease treatments. In Chapter 2 we therefore investigated the role of ILC1s in the pathogenesis of drug-induced acute liver injury. We found that activated liver ILC1s robustly produced interferon (IFN)-g, protecting mice from acute liver injury through the promotion of pro-survival signals in hepatocytes. However, the mechanisms and cell types that led to ILC1 activation were unclear. Therefore, in Chapter 3, we developed a novel method to rapidly study gene function in multiple innate immune cell linages using a CRISPR-Cas9 Ribonucleoprotein (cRNP)-based approach. In Chapter 4, we used this system to dissect the liver-resident immune cell types and interactions that regulate early sterile inflammation during acute liver injury. We identified tissue-resident cDC1s and cDC1-derived Interleukin (IL)-12 as required for protective ILC1 IFN-g signaling. Additionally, using a targeted in vivo cRNP screen, we found that activation cGAS-STING signaling was required for IL-12 production and initiation of protective responses. To determine whether cDC1s initiate sterile inflammation through a conserved mechanism that can have differential effects in the acute versus chronic contexts, we developed a model of chronic sterile inflammation using diet-induced obesity. In Chapter 5, we generated a large scale, high-dimensional atlas of sorted human immune cells derived from healthy lean and obese patient white adipose tissue (WAT) to define the changes in immune composition and signaling networks that are associated with human obesity. Our analysis discovered 8 previously uncharacterized cell types and revealed distinct obesity-associated inflammatory interactions enriched in WAT-resident immune cells. Finally, in Chapter 6, we performed a comparative analysis of mouse and human obese single cell RNA-sequencing datasets, demonstrating that activated cDC1s act as conserved central regulators of obesity-associated sterile inflammation. We found that cDC1s contribute to WAT inflammation and systemic metabolic dysfunction through cGAS-STING-mediated production of IL-12 and subsequent activation of ILC1 IFN-g signaling. Together, these results suggest a novel role for cDC1s in the initiation of both acute and chronic sterile inflammation and highlight the importance of context-dependent analysis of cell function.

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This item is under embargo until March 7, 2025.