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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM038765-28
Application #
8688494
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Okita, Richard T
Project Start
1987-07-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
28
Fiscal Year
2014
Total Cost
$431,528
Indirect Cost
$181,528
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Sorokin, Alexander V; Yang, Zhi-Hong; Vaisman, Boris L et al. (2016) Addition of aspirin to a fish oil-rich diet decreases inflammation and atherosclerosis in ApoE-null mice. J Nutr Biochem 35:58-65
Zhu, Mingqin; Wang, Xiuzhe; Hjorth, Erik et al. (2016) Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase Aβ42 Phagocytosis. Mol Neurobiol 53:2733-49
Dalli, Jesmond; Vlasakov, Iliyan; Riley, Ian R et al. (2016) Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages. Proc Natl Acad Sci U S A 113:12232-12237
Hodges, Robin R; Li, Dayu; Shatos, Marie A et al. (2016) Lipoxin A4 Counter-regulates Histamine-stimulated Glycoconjugate Secretion in Conjunctival Goblet Cells. Sci Rep 6:36124
Hodges, R R; Li, D; Shatos, M A et al. (2016) Lipoxin A4 activates ALX/FPR2 receptor to regulate conjunctival goblet cell secretion. Mucosal Immunol :
Dalli, Jesmond; Serhan, Charles (2016) Macrophage Proresolving Mediators-the When and Where. Microbiol Spectr 4:
Arnardottir, Hildur H; Dalli, Jesmond; Norling, Lucy V et al. (2016) Resolvin D3 Is Dysregulated in Arthritis and Reduces Arthritic Inflammation. J Immunol 197:2362-8
Colas, Romain A; Dalli, Jesmond; Chiang, Nan et al. (2016) Identification and Actions of the Maresin 1 Metabolome in Infectious Inflammation. J Immunol 197:4444-4452
Chiang, Nan; de la Rosa, Xavier; Libreros, Stephania et al. (2016) Novel Resolvin D2 Receptor Axis in Infectious Inflammation. J Immunol :
Elajami, Tarec K; Colas, Romain A; Dalli, Jesmond et al. (2016) Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. FASEB J 30:2792-801

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