Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms

Abstract

Practitioners of ancient societies from the time of Hippocrates and earlier recognized and treated the signs of inflammation, heat, redness, swelling, and pain with agents that block or inhibit proinflammatory chemical mediators. More selective drugs are available today, but this therapeutic concept has not changed. Because the acute inflammatory response is host protective to contain foreign invaders, much of today's pharmacopeia can cause serious unwanted side effects, such as immune suppression. Uncontrolled inflammation is now considered pathophysiologic and is associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity, and asthma, as well as classic inflammatory diseases (e.g., arthritis and periodontal diseases). The inflammatory response, when self-limited, produces a superfamily of chemical mediators that stimulate resolution of the response. Specialized proresolving mediators (SPMs), identified in recent years, are endogenous mediators that include the n-3-derived families resolvins, protectins, and maresins, as well as arachidonic acid-derived (n-6) lipoxins, which promote resolution of inflammation, clearance of microbes, reduction of pain, and promotion of tissue regeneration via novel mechanisms. Aspirin and statins have a positive impact on these resolution pathways, producing epimeric forms of specific SPMs, whereas other drugs can disrupt timely resolution. In this article, evidence from recent human and preclinical animal studies is reviewed, indicating that SPMs are physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. The findings suggest that it is time to challenge current treatment practices-namely, using inhibitors and antagonists alone-and to develop immunoresolvents as agonists to test resolution pharmacology and their role in catabasis for their therapeutic potential.-Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms.

Keywords: leukocytes; lipoxins; maresins; omega-3 PUFA; protectins; resolvins.

Figure 1.

Eicosanoids and proresolving mediators in the inflammatory response. Time-course illustration of the key roles of lipid mediators in the initiation and resolution of acute inflammation. Eicosanoids function and contribute to cardinal signs of inflammation. Prostaglandin E₂ (PGE₂) and PGI₂ permit neutrophils to transmigrate from postcapillary venules across endothelial cells to migrate and chemotax along a gradient of leukotriene B₄ (LTB₄), a potent chemoattractant. Lipid mediator class switching occurs as neutrophils congregate in pus or purulent exudates (see text and ref. for details). Lipoxins (LXs) stimulate nonphlogistic monocyte recruitment. LXs, resolvins (Rvs), and other specialized proresolving mediators (SPMs) are produced in pus to limit or stop further neutrophil tissue infiltration. SPMs, Rvs, maresins (MaRs), and protectins, each stimulate efferocytosis of apoptotic neutrophils and cellular debris by macrophages. Resolving macrophages and apoptotic neutrophils also produce SPMs (see ref. 135). Edema also brings circulating n-3 polyunsaturated fatty acids (PUFAs) [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] into exudates for temporal conversion to SPMs by exudate cells (85). SPMs stimulate the signs of resolution and resolve exudates (33). Rvs and SPMs block chronic inflammation and reduce fibrosis. MaRs and specific Rvs enhance wound healing and tissue regeneration.

Figure 2.

Human SPM biosynthetic routes. Biosynthesis of E-series Rvs is initiated with molecular oxygen insertion at carbon-18 position of EPA, which is converted to bioactive E-series members RvE1–E3. The resolution metabolome also activates 17-lipoxygenation of DHA; 17S-HpDHA is converted to Rv-epoxide intermediates by the leukocyte 5-LOX. The intermediates are transformed to RvD1–D6, each of which carries potent actions. 17-HpDHA is also the precursor to the 16,17-epoxide-PD intermediate, which is converted to NPD1/PD1 and related PDs (see Fig. 6A). MaRs are produced by macrophages via initial lipoxygenation at the carbon-14 position by lipoxygenation and insertion of molecular oxygen, producing a 13S,14S-epoxide-MaR intermediate that is enzymatically converted to the MaR family members MaR1, MaR2, and MCTRs. The stereochemistry of each bioactive SPM has been established, and SPM biosynthesis in murine exudates and human tissues confirmed. (See refs. , , , for original reports, total organic synthesis, and stereochemical assignments and the text for further details. For complete stereochemistry of individual SPMs, see refs. , , .) Low-dose aspirin triggers the 17R and 18R/S epimers of the Rvs (9, 53) and 17R-epimer PDs (165, 166).

Figure 3.

Rvs and SPMs in the cellular resolution pathway. SPMs stimulate efferocytosis and the uptake of debris for successful clearance from tissues and resolution. SPMs block NF-κB; inhibition of containment of apoptotic cells leads to secondary necrosis and chronic inflammation (see text and ref. for further details). SPMs counterregulate proinflammatory mediators and growth factors, cytokines, LTs, and PGs.

Figure 4.

Steps to human translation of SPMs. Timeline illustration of the key steps from identification in self-limited resolving exudates and function, structural elucidation, and biosynthesis, to single-cell actions and preclinical disease models with birth of resolution indices and resolution pharmacology for these endogenous autacoid mediators.

Figure 5.

Resolving exudates produce chemical signals to link system needs. Chemical signals produced by resolving exudate leukocytes act in host defense to reduce pain, enhance wound healing and tissue regeneration, and act on cells of the adaptive immune system.

Figure 6.

A) Biosynthesis and structural elucidation of SPM conjugates in tissue regeneration. DHA is the substrate to production of epoxide intermediates in 3 separate pathways that are conjugated via glutathione-S-transferase to give novel mediators that are proresolving and potent mediators in tissue regeneration (see text for details). B) Conserved chemical structure of the epoxide intermediate. Results of the studies of tissue regeneration and resolution, when viewed together with those of earlier studies of LTs, indicate that the allylic epoxide depicted is produced via LOX reactions and abstraction of hydrogen from a hydroperoxide precursor made from 1,4-cis-penta-diene-containing essential fatty acids and a pivotal functional unit in cell signaling to produce proinflammatory LTs and the bronchoconstrictor SRS-A and SPMs that are temporally dissociated as well as cell-type specific in their function and actions.