Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators

Abstract

Protection versus uncontrolled inflammation: first responders and resolutionNew evidence indicates that uncontrolled inflammation is a prominent component of many common diseases, including wellknown inflammatory diseases such as arthritis and periodontal disease as well as inflammatory bowel disease, cardiovascular disease, the neurodegenerative diseases Alzheimer's and Parkinson's, asthma, cancer, metabolic syndromes (e.g., obesity), diabetes, and autoimmune diseases (https://www.cdc.gov).In each, peripheral blood markers of inflammation are present and elevated (1).Aging and proinflammatory nutrition (2, 3) also contribute to increases in inflammatory markers.Thus, the impact of uncontrolled inflammation on the United States alone is estimated in hundreds of millions of dollars for each disease, with substantial increases by 2030 -certainly, epidemic proportions.The acute inflammatory response is protective.Among the first responders, neutrophils (polymorphonuclear leukocytes [PMNs]) leave postcapillary venules to phagocytize microbes and cellular debris (4).PMNs neutralize and clear invaders; however, when excess PMNs congregate or swarm in tissues (5), they can inadvertently release their antimicrobial armamentarium via frustrated phagocytosis or cell death (4, 6), leading to tissue damage that amplifies inflammation and continues to chronicity.PMN-driven inflammation is a unifying mechanism for many diseases and reperfusion second-organ injury (4).Hence, it is critical to appreciate mechanisms and specialized mediators (7) involved in resolution and whether we can use these to control inflammation.In health, acute inflammatory response(s) are self-limited, as in surgery-induced tissue injury, in that they resolve on their own and classically divide into initiation and resolution phases (4).To date, we view acute inflammation as a temporal crescendo to resolution and decrescendo of initiating chemical mediator gradients (7).In resolution (Figure 1), the host response is active (7) and not simply a passive dilution of proinflammatory mediators (8), enabling tissues to restore function (4).Lipoxins biosynthesized from arachidonic acid are potent, active stop signals for PMN infiltration (9, 10) and are produced during resolution of self-limited inflammatory responses (11,12).While current treatments for inflammation can be effective, many eventually become immunosuppressive opportunities for infection.Chemical mediators such as prostaglandins physiologically mediate the cardinal signs of inflammation (color, rubor, tumor, dolor) and are effectively controlled by traditional NSAIDs (13); however, NSAIDs are not without unwanted side effects.Given the significant public health impact of inflammation-associated diseases, it is paramount to seek new treatments and mechanisms controlling inflammation and collateral tissue damage from excessive PMN swarming (5).In Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury.These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation.Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer.While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation.Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs.This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process.These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective.We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies.