Omega-3 Fatty Acid-Derived Mediators 17(R)-Hydroxy Docosahexaenoic Acid, Aspirin-Triggered Resolvin D1 and Resolvin D2 Prevent Experimental Colitis in Mice

Abstract

Resolvins of the D series are generated from docosahexaenoic acid, which are enriched in fish oils and are believed to exert beneficial roles on diverse inflammatory disorders, including inflammatory bowel disease (IBD). In this study, we investigated the anti-inflammatory effects of the aspirin-triggered resolvin D1 (AT-RvD1), its precursor (17(R)-hydroxy docosahexaenoic acid [17R-HDHA]) and resolvin D2 (RvD2) in dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Our results showed that the systemic treatment with AT-RvD1, RvD2, or 17R-HDHA in a nanogram range greatly improved disease activity index, body weight loss, colonic damage, and polymorphonuclear infiltration in both colitis experimental models. Moreover, these treatments reduced colonic cytokine levels for TNF-α, IL-1β, MIP-2, and CXCL1/KC, as well as mRNA expression of NF-κB and the adhesion molecules VCAM-1, ICAM-1, and LFA-1. Furthermore, AT-RvD1, but not RvD2 or 17R-HDHA, depended on lipoxin A4 receptor (ALX) activation to inhibit IL-6, MCP-1, IFN-γ, and TNF-α levels in bone marrow-derived macrophages stimulated with LPS. Similarly, ALX blockade reversed the beneficial effects of AT-RvD1 in DSS-induced colitis. To our knowledge, our findings showed for the first time the anti-inflammatory effects of resolvins of the D series and precursor 17R-HDHA in preventing experimental colitis. We also demonstrated the relevant role exerted by ALX activation on proresolving action of AT-RvD1. Moreover, AT-RvD1 showed a higher potency than 17R-HDHA and RvD2 in preventing DSS-induced colitis. The results suggest that these lipid mediators possess a greater efficacy when compared with other currently used IBD therapies, such as monoclonal anti-TNF, and have the potential to be used for treating IBD.

Resolvins D1, D2, and Other Mediators of Self-Limited Resolution of Inflammation in Human Blood following n-3 Fatty Acid Supplementation

“…An important finding of our study is that the concentrations of the potent antiinflammatory and proresolving agents RvD1 and RvD2 detected in blood from healthy humans after n-3 fatty acid supplementation for 3 weeks are within the bioactive range observed in isolated human leukocytes (21,22 ) and in in vivo studies in mice (12,23 ).…”

“…RvD1 provides protection against renal injury after ischemia reperfusion (26 ) and prevents neutrophil recruitment in peritonitis (27 ) and the dorsal skin air pouch (22 ). 17R-RvD1 is effective in preventing experimental colitis in the mouse (12 ). RvD2 is a potent regulator of leukocytes.…”

“…2) (2)(3)(4)(5). These mediators, acting via G-coupled protein receptors (6 ), have potent antiinflammatory and proresolving actions (7,8 ) and reduce airway inflammation (9,10 ), dermal inflammation (11 ), colitis (12 ), arthritis (13 ), and postoperative pain (14 ). Studies have shown that these mediators increase with time during the inflammatory process (1,15 ).…”

Ligand-specific conformational change of the G-protein–coupled receptor ALX/FPR2 determines proresolving functional responses

“…A detailed understanding of the importance of dimerization evoked by proresolving agonists AnxA1 and LXA 4 to ALX biology will clarify the impact of this receptor on the therapeutic control of pathogenic states. For instance, this conformational alteration of ALX may be relevant for the proresolving properties of resolvin D1 as described in models of colitis (38). Finally, our unique data can guide the development of synthetic ALX agonists, including stable LXA 4 analogs (39), peptide mimetics (40), or small molecules (41), with the ultimate goal of developing innovative therapeutics to moderate overexuberant inflammatory responses.…”

Resolvin D1 Polarizes Primary Human Macrophages toward a Proresolution Phenotype through GPR32

“…These proresolution properties on the cellular level were corroborated in several mouse models of inflammation. RvD1 was shown to reduce inflammatory pain (14,15), to be protective for airway inflammation (16), to reduce second organ injury induced by ischemia-reperfusion (11), and it enhanced wound healing and suppressed colitis in mouse models of inflammatory diseases (17). RvD1 also lowered adipose tissue inflammation and ameliorated insulin sensitivity in mouse models of obesity by modifying cytokine and adipokine production in adipose tissue, which led to a reduction in macrophage number and in the inflammation state of the fat tissue (18,19).…”