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. 2013 Jan 30:4:13.
doi: 10.3389/fimmu.2013.00013. eCollection 2013.

Omega-3 fatty acid-derived resolvins and protectins in inflammation resolution and leukocyte functions: targeting novel lipid mediator pathways in mitigation of acute kidney injury

Song Hong  1 , Yan Lu
Affiliations

Omega-3 fatty acid-derived resolvins and protectins in inflammation resolution and leukocyte functions: targeting novel lipid mediator pathways in mitigation of acute kidney injury

Song Hong et al. Front Immunol. .

Abstract

Inflammation, in conjunction with leukocytes, plays a key role in most acute kidney injury (AKI). Non-resolving renal inflammation leads to chronic fibrosis and renal failure. Resolvin D series (RvDs) and E series (RvEs), protectins, and maresins (MaRs) are endogenous omega-3 fatty acid-derived lipid mediators (LMs) that potently promote inflammation resolution by shortening neutrophil life span and promoting macrophage (Mf) non-phelogistic phagocytosis of apoptotic cells and the subsequent exit of Mfs from inflammatory tissue. 14S,21R-dihydroxy docosahexaenoic acid (14S,21R-diHDHA), a Mf-produced autacrine, reprograms Mfs to rescue vascular endothelia. RvD1, RvE1, or 14S,21R-diHDHA also switches Mfs to the phenotype that produces pro-resolving interleukin-10. RvDs or protectin/neuroprotectin D1 (PD1/NPD1) inhibits neutrophil infiltration into injured kidneys, blocks toll-like receptor -mediated inflammatory activation of Mfs and mitigates renal functions. RvDs also repress renal interstitial fibrosis, and PD1 promotes renoprotective heme-oxygenase-1 expression. These findings provide novel approaches for targeting inflammation resolution and LMs or modulation of LM-associated pathways for developing better clinical treatments for AKI.

Keywords: 14S,21R-diHDHA; fibrosis; inflammation-resolution; kidney-injury; leukocytes; maresins; protectins/neuroprotectins; resolvins.

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Figures

Figure 1
Figure 1
Role of lipid mediators, resolvins and protectins in inflammation resolution in acute renal injury (AKI). AKI causes (1) damage of renal vascular endothelium; (2) diapedesis of neutrophils and monocytes through endothelium; (3) accumulation of neutrophils, macrophages (Mfs), dendritic cells (DCs), T cells, fibroblasts, and myofibroblasts in renal tissue; and (4) apoptosis and necrosis of tubular epithelium. Impaired inflammation resolution that occurs during AKI leads to chronic fibrosis [i.e., excessive extracellular matrix (ECM, as light-green lines) produced by myofibroblasts and other cells in the kidneys] and ultimately chronic renal failure (Bonventre and Yang, ; Serhan and Petasis, 2011). Although leukocytes cause tissue damage when activated to inflammatory phenotypes by AKI in the initial phase, they could promote inflammation resolution and tissue repair when modulated by pro-resolving lipid mediators, including resolvins and protectins. Resolvins, protectins, maresins, and 14S,21R-diHDHA are produced by 12/15-lipoxygenase (LO), p450, and/or 5-LO, in trans-cellular or intracellular biosynthetic systems of leukocytes or leukocytes plus endothelia/epiothelia. These lipid mediators act as paracrines and autacrines of leukocytes to promote resolution of AKI-initiated inflammation and fibrosis and rescue of kidney functions. They also inhibit accumulation of neutrophils and Mfs in kidneys during acute inflammation in AKI (Duffield et al., ; Tian et al., 2012), promote Mf non-phlogistic efferocytosis of apoptotic neutrophils (Hong et al., 2008), enhance apoptotic leukocyte expression of CCR5 that scavenges critical inflammatory chemokines, and accelerate phagocyte exit from the inflammatory site via the lymphatics (Ariel et al., ; Ariel and Serhan, 2007). These lipid mediators increase the level of pro-resolving, anti-fibrotic IL-10 and reduce the levels of inflammatory cytokines TNFα, IL-1β, IL-6, and/or IL-8 in Mfs or renal tissue. Thus these lipid mediators act as effectors for inflammation resolution and injury repair, which restores AKI-damaged kidneys to homeostasis. Administration of these lipid mediators promotes resolution of inflammation and injury in AKI.
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