Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function

Abstract

Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators - specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids - which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways.

Fig. 1. Adiporenal axis in CKD.

In the context of excess calorie intake, the body’s capacity to store fat in adipose tissue is exceeded and multiorgan ectopic lipid accumulation ensues. This situation is characterized by adipocyte hypertrophy, insulin resistance, dysregulation of inflammatory cytokines and adipokines, and the recruitment of macrophages and other immune cells to the inflamed adipose tissue. Adipose tissue-derived leptin, tumour necrosis factor (TNF), IL-6, IL-1β, interferon-γ (IFNγ), and C-C motif chemokine 2 (CCL2/MCP1) stimulate pro-inflammatory signalling pathways in multiple organs, including the kidneys. Renal lipotoxicity occurs in all major kidney cell populations, including mesangial cells, podocytes and proximal tubule epithelial cells. Lipid accumulation within the kidney is mediated, in part, via the scavenger receptor CD36, leading to activation of multiple inflammatory pathways, including those mediated via Toll-like receptors, NLRP3 inflammasome and TGFβ signalling. The overall burden of lipotoxic effects caused by the ectopic accumulation of lipids and adipokines in the kidney results in oxidative stress, activation of the renin–angiotensin aldosterone system (RAAS), inflammation and fibrosis, ultimately leading to glomerular and tubular compartment damage. FFA, free fatty acid; iNKT, invariant natural killer; LTB₄, leukotriene B₄.

Fig. 2. Cellular mechanisms and inflammatory pathways in kidney disease, and cellular targets of specialized pro-resolving lipid mediators.

a | As a consequence of diabetes, prolonged hyperglycaemia, dyslipidaemia and hypertension drive multiorgan damage. In the kidney, for example, pro-inflammatory signalling contributes to glomerular and tubular damage and altered kidney morphology and function. The production of growth factors (for example, transforming growth factor-β1, platelet-derived growth factor and connective tissue growth factor), as well as pro-inflammatory mediators (for example, IL-1β, IL-6, monocyte chemoattractant protein-1, nuclear factor κB and tumour necrosis factor) by infiltrating leukocytes and resident kidney cells lead to kidney damage via mesangial cell activation and proliferation, tubule epithelial cell damage and disruption of the tubular basement membrane, glomerular endothelial dysfunction, and podocyte effacement and loss. b | Key aspects of this process that might be modulated by specialized pro-resolving lipid mediators include leukocyte recruitment and activation^,, dedifferentiation of epithelial cells within the kidney tubule^,,, glomerular endothelial cell and myofibroblast activation^,,,, podocyte foot process effacement, M1 to M2 macrophage phenotype shifts^,, and mesangial cell activation and matrix accumulation^,,,,. AGE-RAGE, advanced glycation end-products–receptor for advanced glycation end-products; ECM, extracellular matrix; LX, lipoxin; MaR, maresin; PD, protectin; Rv, resolvin; sLX, synthetic lipoxin.

Fig. 3. Inflammation resolution and biosynthesis of specialized pro-resolving lipid mediators from ω-6 and ω-3 polyunsaturated fatty acids.

During the early initiation phase of inflammation, local production of pro-inflammatory cytokines (for example, TNF, IL-1β and IL-6) and eicosanoids promotes the recruitment of neutrophils to the site of tissue injury. Here, cyclooxygenase (COX) and lipoxygenase (LO) enzymes catalyse the conversion of the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid into a series of pro-inflammatory mediators, including prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs). Subsequently, a ‘class switch’ in lipid mediator biosynthesis occurs via a process involving the prostaglandins generated in the initiation phase of inflammation, leading to the synthesis of specialized pro-resolving lipid mediators (SPMs) and the resolution phase of inflammation. The ω-6 PUFA arachidonic acid produces lipoxins (LXs) and aspirin-triggered lipoxins (15-epi-LXs). The ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are precursors of a series of lipid mediators including resolvins (RVs), protectins (PD) and maresins (MaRs). 18S-E-series (18S-RvE1 and 18S-RvE2) resolvins and MaR conjugates in tissue regeneration (MCTR) have also been discovered, which are derived from the Rv and MaR biosynthesis pathways, respectively. Aspirin acetylation of COX-2 leads to distinct SPM biosynthetic pathways from arachidonic acid, EPA and DHA. These aspirin-triggered (AT) SPMs show the same biological actions as the native mediators.

Fig. 4. Transcellular pathways of specialized pro-resolving lipid mediator synthesis.

The formation of specialized pro-resolving lipid mediators (SPMs) is achieved via transcellular biosynthesis. This highly coordinated process requires contributions from enzymes (for example, lipoxygenase (LO)-resident and cyclooxygenase 2 (COX-2)-resident endothelial cells, epithelial cells and polymorphonuclear cells (PMN) and platelets at the site of inflammation. SPMs can be derived from arachidonic acid (AA) (part a), eicosapentaenoic acid (EPA) (part b) and docosahexaenoic acid (DHA) (part c). 18S-RvE, 18S E-series resolvins; ASA, acetylsalicylic acid (aspirin); AT-PD1, aspirin-triggered protectin D1; AT-RvD, aspirin-triggered D-series resolvins; ATLs, aspirin-triggered lipoxins; LXA₄, lipoxin A₄; LXB₄, lipoxin B₄; RvD, D-series resolvins; RvE, E-series resolvins; MaR, maresins; PD1, protectin D1.

Fig. 5. Regulation of inflammation through ALX/FPR2.

Both pro-inflammatory and anti-inflammatory (pro-resolving) signals are mediated by the G protein-coupled receptor ALX/FPR2 (referred to as FPR2 in the figure). Endogenous ligands at this receptor include ω-3 and ω-6 polyunsaturated fatty acid-derived anti-inflammatory lipids (lipoxin A₄ (LXA₄), 15-epi-lipoxin A₄ (ATL) and resolvin D1 (RvD1). Protein ligands with anti-inflammatory effects (for example, annexin A1 (AnxA1); annexin A1-derived peptide Ac2-26) and pro-inflammatory effects (for example, serum amyloid A (SAA)) have also been described. Ligand–receptor interactions are believed to occur at distinct receptor pockets, with different affinities. ALX/FPR2 homodimers and ALX/FPR2–FPR1 heterodimers eliciting pro-resolving and pro-inflammatory effects have been described. ALX/FPR2 receptor internalization is essential for LXA₄-stimulated and AnxA1-stimulated phagocytosis. Crosstalk has also been reported between ALX/FPR2 and several receptor kinases implicated in organ fibrosis, including transforming growth factor-β1 receptor (TGFβR1), platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR).

Fig. 6. Role of specialized pro-resolving lipid mediators in the resolution of inflammation.

Specialized pro-resolving lipid mediators (SPMs) are biosynthesized at the site of tissue injury via interactions between resident endothelial and/or epithelial cells and infiltrating polymorphonuclear cells (PMN). SPMs exert their actions via engaging with specific pro-resolving G protein-coupled receptors expressed on resident tissue cells and PMNs. Pro-resolving SPM bioactions include attenuation of endothelial cell activation, blocking of neutrophil extravasation, promoting non-phlogistic monocyte recruitment, promoting an (M2) resolving macrophage phenotype, and stimulating neutrophil apoptosis and macrophage efferocytosis. SPMs are produced by, and act on, stem cells, and evidence suggests that SPMs mediate the immunomodulatory and anti-inflammatory effects of these cells. PGs, prostaglandins; LTs, leukotrienes.