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

Abstract

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.

Conflict of interest statement

Conflict of interest: The authors are inventors on patent applications and awarded patents assigned to Brigham and Women’s Hospital; some are licensed for clinical development (US patents 7,585,856; 6,670,396; 7,053,230; 7,709,669; 7,737,178; 8,349,896; 7,030,159; 7,741,368; 7,341,840; 7,803,557; 8,927,747; 9,611,238; 9,611,239; and 9,611,240 to CNS; and US patents 7,759,395; 7,872,152; 8,569,542; 8,933,270; 7,759,395; 7,872,152; 8,569,542; 8,273,792; 8,273,792; and 8,933,270 to CNS and BDL).

Figures

Figure 1. Acute inflammatory response and its ideal outcome: complete resolution.

(A) Temporal lipid mediator class-switching initiates active resolution and SPM biosynthesis. Defined steps in the acute inflammation time course: edema, PMN infiltration, and then non-phlogistic monocyte-macrophage recruitment to inflammatory exudates. The reduction in PMN number coincides with the exudate appearance of SPMs and with the biosynthesis of lipoxins, resolvins (E- and D-series), protectins, and maresins in resolving exudates. (B) Each family of SPMs is structurally distinct and possesses potent pro-resolving actions.

Figure 2. SPM network biosynthetic metabolomes.

Network illustration of the enzymes, intermediates, and precursors of the SPM superfamily’s biosynthesis from omega-3 PUFA. Deficiencies in the fatty acid desaturase (Fads) gene cluster reduce SPM production (194). Stereochemistry of each major SPM is established; for detailed mechanisms in biosynthesis and complete SPM nomenclature of each endogenous molecule, see refs. , , –, and 58 and those within.

Figure 3. Quantitative definition of exudate resolution and non-resolving inflammation.

Hypothetical example of contained self-limited resolving inflammation versus non-resolving inflammation (red line) to illustrate the quantitative indices and components: ψmax for peak PMN infiltration, 50% of peak PMN (R50), time point of R50 (T50), and resolution interval (Ri) to quantitate PMN influx and removal as well as non-phlogistic recruitment of monocytes-macrophages in exudates, which is required for repair and renewed function. See text and refs. and for original results and definitions.