Novel Resolution Mediators of Severe Systemic Inflammation

Abstract

Nonresolving inflammation, a hallmark of underlying severe inflammatory processes such as sepsis, acute respiratory distress syndrome and multiple organ failure is a major cause of admission to the intensive care unit and high mortality rates. Many survivors develop new functional limitations and health problems, and in cases of sepsis, approximately 40% of patients are rehospitalized within three months. Over the last few decades, better treatment approaches have been adopted. Nevertheless, the lack of knowledge underlying the complex pathophysiology of the inflammatory response organized by numerous mediators and the induction of complex networks impede curative therapy. Thus, increasing evidence indicates that resolution of an acute inflammatory response, considered an active process, is the ideal outcome that leads to tissue restoration and organ function. Many mediators have been identified as immunoresolvents, but only a few have been shown to contribute to both the initial and resolution phases of severe systemic inflammation, and these agents might finally substantially impact the therapeutic approach to severe inflammatory processes. In this review, we depict different resolution mediators/immunoresolvents contributing to resolution programmes specifically related to life-threatening severe inflammatory processes.

Keywords: immunoresolvents; inflammation; neuronal guidance protein; resolution; sepsis; specialized lipid mediators.

Figure 1

Complete resolution versus failed resolution of acute inflammation. Notes: The endogenous specialized proresolving mediators (SPMs) control key actions of resolution, including leukocyte trafficking, MΦ reprogramming and MΦ phagocytosis/efferocytosis (see text). Abbreviations: MΦ, macrophage; PGD₂, prostaglandin D₂; PGE₂, prostaglandin E₂; PMN, polymorphonuclear leukocytes; SPM, specialized proresolving mediator.

Figure 2

Sympathetic nerve in the resolution of acute inflammation. Notes: The adrenergic nerve together with the neuronal guidance protein RGM-A activate resolution programmes. RGM-A enhances the expression of the β2 adrenergic receptor (β2AR) on human MΦs, and activation of β2AR, in turn, increases RGM-A expression on MΦs. This interaction of the β2 adrenergic receptor and RGM-A signalling indicates a stronger reduction in PMN and proinflammatory cytokine levels and a stronger increase in MΦ efferocytosis and phagocytosis compared to that achieved with one agent alone, ultimately resulting in the generation of proresolving mediators. Abbreviations: AKT, protein kinase B; ALX, N-formyl peptide receptor 2; GPR32, G protein-coupled receptor 32; MФ, macrophage; M1, classically activated/type 1 proinflammatory macrophages; M2, alternatively activated/type 2 anti–inflammatory macrophages; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphoinositide 3-kinase; PMN, polymorphonuclear leukocytes; SPM, specialized proresolving mediator.

Figure 3

Actions of neuronal guidance proteins RGM-A and Netrin-1 during the resolution of inflammation. Notes: In the initial phase of inflammation, RGM-A and Netrin-1 dampen PMN infiltration through their chemorepulsive attributes. In the resolution phase, they induce a reduction in proinflammatory Ly6C^hi numbers, an increase in anti–inflammatory Ly6C^lo monocyte numbers and a subsequent switch from the M1 to M2 phenotype. RGM-A and Netrin-1 activate the generation of proresolving lipid mediators and, ultimately, tissue clearance through the macrophage efferocytosis/phagocytosis of neutrophils and inflammatory particles, finally leading to organ regeneration. Abbreviations: Ly6C^hi, classical (proinflammatory) monocytes; Ly6C^lo, non-classical (anti–inflammatory) monocytes; M1, classically activated/type 1 proinflammatory macrophages; M2, alternatively activated/type 2 anti–inflammatory macrophages PMN, polymorphonuclear leukocytes; RGM-A, repulsive guidance molecule A.