Human phagocytes, the major white blood cells [neutrophils (PMN) and macrophages (M?)], control host defenses, local inflammation and its timely resolution. Little is known about the endogenous mediators and mechanisms that govern resolution of these processes. This proposal's overall goal is to establish novel endogenous resolution circuits because it is now clear that unresolved inflammation is linked to many widely occurring human diseases including cardiovascular, neurologic disorders, and classic inflammatory diseases. Resolution of acute inflammation was believed to be passive. Support from GM38765 permitted us to obtain the first evidence demonstrating that resolution of acute inflammation is an active temporally coordinated process with the identification of a novel genus of specialized pro-resolving mediators (SPM). The genus includes resolvins (Rv), protectins (PD) and their aspirin-triggered (AT) forms biosynthesized from essential omega-3 fatty acids (n-3 EFA) and a recently identified family of mediators coined maresins (MaR) that regulate both PMN and M? responses critical for resolution. SPM are potent stereoselective agonists that are anti-inflammatory, pro-resolving and stimulate host anti-microbial mechanisms. This proposal is based on new findings from work in progress where we uncovered a novel neural-phagocyte resolution circuit that produces endogenous D-series resolvins via phagocytes. The unique features and innovation in this proposal include systematic elucidation of resolution pathway components activated in self-limited inflammation using an unbiased mediator-lipidomics approach together with resolution indices to address exudate tracking of leukocytes and chemical mediators. Our mission is to elucidate signals that activate resolution circuits. We propose to test the following new hypothesis: Local specialized pro-resolving mediators (SPM) produced by exudate phagocytes required for timely resolutions are stimulated by neuronal signals. Resolvins, specifically resolvin D2 (RvD2), a newly elucidated resolvin, is a potent agonist that governs local phagocyte resolution responses via novel pro-resolving receptors required for homeostasis and effective microbial clearance. To address this, 4 specific aims are proposed to establish: 1) vagus activation of innate phagocyte resolvins and resolution pathways;2) novel resolvin D2 pro-resolving receptor circuit;3) functional validation of RvD2- specific pro-resolving receptors;and 4) resolvin receptors on human phagocytes during disease. Because new anti-inflammatories that are not immunosuppressive are needed, our results from these innovative studies will affect this scientific area and patient care by providin rigorous evidence for novel resolution circuits and molecular mechanisms for controlling local inflammation via activating endogenous resolution. Long-term objectives include providing novel mechanisms for clinicians to activate resolution and improve treatment practices for diseases characterized by ungoverned inflammation.
Inflammation is protective, yet when uncontrolled, inflammation is now widely recognized as a link that underlies many chronic diseases (including diabetes, periodontal disease, arthritis, cardiovascular diseases, decline in cognitive function and aging. This research is relevant to public health because the proposed studies focus on the identification of the body's own mechanisms that resolve the acute inflammatory response via novel pathways and mediators used by white blood cells to return to normal.
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