Thursday, June 8, 2023
6/8/2023
Chronic inflammation is a common pathological basis for age-associated increases in autoimmunity, diabetes, cancer, cardiovascular and Alzheimer’s disease as well as shortened lifespan. Failure to resolve an activated innate immune response contributes significantly to chronic inflammation. Despite the profound clinical implications, the specific innate pathways contributing to chronic inflammation remain unknown. We reasoned that age-associated accrual of damaged DNA, which in other settings is a known driver of inflammation through cell-intrinsic DNA-sensing pathways, may contribute to age-associated chronic inflammation through these same innate pathways. Notably, cell-intrinsic DNA-sensing pathways require the participation of the DNA-sensor, cGAS and ER-resident adaptor, STING and are potent inducers of the pleiotropic cytokine family, type I interferons (IFN-I). IFN-I have been linked to chronic inflammation in disorders such as autoimmunity and cancer. While the molecular components of age-associated chronic inflammation remain undefined, a significant body of work suggests that recirculating innate cells may be compromised, however, the contribution of tissue resident macrophages to aging has not been addressed. Tissue macrophages are distinct from other myeloid-derived cells, not only in their origins, but also because they integrate epigenetic and microenvironment cues to carry out a unique set of functions. In addition to mounting innate immune responses, tissue macrophages are indispensable for tissue patterning, resolution of inflammation and tissue repair. Here we propose to test the hypothesis that cytosolic DNA-sensing promotes constitutive IFN-I induction within tissue macrophages and drives age-associated chronic inflammation. We will systematically address how specific innate processes contribute to immune dysfunction in the elderly in three specific aims. 1) We will evaluate the contribution of cytosolic DNA-sensing pathways to aging-associated constitutive IFN-I and proinflammatory signatures in tissues and resident macrophages using mice deficient in cGAS and STING. 2) We will determine the direct contribution cytosolic DNA sensing pathways in exclusively shaping tissue macrophage fate and function with age by conditionally deleting STING directly in tissue macrophage progenitors. As the epigenomes and transcriptomes of tissue macrophages are highly plastic, we will utilize next generation sequencing to identify genome-wide changes instigated by cytosolic DNA-sensing pathways in these cells with progressive age. 3) Finally, we will extend our findings to humans and determine the baseline IFN-I signatures and responsiveness of tissue macrophages from the lungs of geriatric patients and correlate them to well-represented loss-of-function haplotypes of STING. By uncovering the molecular details of chronic inflammation in aging humans, the findings from this study offer new immunomodulatory strategies and targets to bolster protective immunity as well as block detrimental inflammation, as desired, during aging.
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