Proresolving lipid mediators and mechanisms in the resolution of acute inflammation

Abstract

Inflammatory responses, like all biological cascades, are shaped by a delicate balance between positive and negative feedback loops. It is now clear that in addition to positive and negative checkpoints, the inflammatory cascade rather unexpectedly boasts an additional checkpoint, a family of chemicals that actively promote resolution and tissue repair without compromising host defense. Indeed, the resolution phase of inflammation is just as actively orchestrated and carefully choreographed as its induction and inhibition. In this review, we explore the immunological consequences of omega-3-derived specialized proresolving mediators (SPMs) and discuss their place within what is currently understood of the role of the arachidonic acid-derived prostaglandins, lipoxins, and their natural C15-epimers. We propose that treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation.

Figure 1. Acute Inflammatory Response and the Role of Lipid Mediators in Resolution or its Failure

Initiation of the acute response starts with changes in blood flow stimulated by PGE₂ and PGI₂, and LTB₄, which is produced from arachidonic acid, stimulates PMN recruitment. Excess prostaglandins and leukotrienes contribute to chronic inflammation. Cyclooxygenase (COX) production of PGD₂ via human PGD₂ synthase (hPGD₂s) activates its receptor DPI, a GPCR that stimulates IL-10 and anti-inflammatory cytokine, which blocks the path to chronic inflammation. PGD₂ can be converted to PGJ₂ and 15-dPGJ₂ to products that activate PPARγ to activate resolution (see text for details). Lipid mediator class switching is the temporal switch in inflammatory exudates that activates lipoxin production. LXA₄ regulates MCP-1 and non-phlogistic monocyte recruitment and stops LTB₄-stimulated PMN influx. Lipoxins and resolvins limit PMN further influx to the site and stimulate efferocytosis and the clearance of cellular debris by resolving macrophages. Resolvins, protectins, lipoxins and maresins (SPM) stimulate and enhance efferocytosis and promote resolution. Loss of any of the cell types receptors or chemical mediators can in theory lead to failed resolution that may underlie the persistent inflammation recognized as chronic inflammation associated with many diseases.

Figure 2. Time Course of Self-Limited Inflammatory Response and the Resolution n-3 Metabolome

Upper panel: The ideal outcome for an acute challenge: edema, followed by PMN influx, then return to baseline and non-phlogistic recruitment of monocytes and macrophages for resolution. The temporal biosynthesis of SPM is initiated by leukocyte congregation within the exudate. In resolution phase, specific miRNA are regulated and some of these are controlled by resolvins in recent studies (see Li et al., 2013 and refs. within). Lower panel: Resolving exudate. The E-series resolvins are biosynthesized from EPA, initiated by oxygen insertion at the 18^th carbon position to produce RvE1 via an epoxide intermediate, RvE2 and RvE3. D-series resolvin biosynthesis is initiated with oxygen insertion at the 17^th carbon position of n-3 DHA. The intermediate 17S-HpDHA is precursor to both protectin and D-series resolvins. Human and mouse macrophages also convert DHA to maresins via oxygen insertion initiated at the 14^th carbon to biosynthesize maresin 1 (MaR1) via a recently identified 13S,14S-epoxy-intermediate that also is bioactive. The biosynthesis steps in human leukocytes and in mice are reviewed in Serhan (2007), and stereochemical assignments with confirmation of their potent pro-resolving actions are reviewed in Serhan and Petasis (2011). Apoptotic PMN resolution phase microparticles resolving macrophages produce SPM (Dalli and Serhan, 2012). By definition, each SPM enhances efferocytosis and resolution in vivo in animal models; see text for details. Also, some SPM stimulate the biosynthesis of other families of SPM. For example, RvE1 stimulates LXA₄ production in mouse lung (Levy and Serhan, 2014).

Figure 3. SPM Actions and Target Cell Type

The defining actions of SPM in the innate response of interest in immunology. The actions to stimulate termination and resolution. The precursors essential polyunsaturated fatty acids (AA, EPA, DHA) are converted by leukocytes to separate chemically distinct families of mediators that stimulate active resolution responses of isolated cell types and tissues in vivo in animal models. Some of the specific target cell types and representative potent actions of the SPM members from each family of related structures are listed. All of these actions of SPMs are stereoselective and in the picogram-nanogram range potency. See Serhan and Chiang (2013) and text for further details.