Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model
David Meriwether, … , Alan M. Fogelman, Srinivasa T. Reddy
David Meriwether, … , Alan M. Fogelman, Srinivasa T. Reddy
Published June 11, 2019
Citation Information: J Clin Invest. 2019;129(9):3670-3685. https://doi.org/10.1172/JCI123700.
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Research Article Gastroenterology

Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model

Abstract

Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn’s-like intestinal inflammation when fed cholate-containing high-fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2-KO but not WT mice. Cox2-MKO increased proinflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2-MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, whereas administration of an LXA4 analog rescued disease in Cox2-MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2-MKO/CCHF and piroxicam-accelerated Il10–/– models of inflammatory bowel disease (IBD) and reduced elevated levels of proinflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2-MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides (a) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine–dependent (oxPAPC-dependent) proinflammatory responses in human macrophages and intestinal epithelium, and (b) directly cleared proinflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for proinflammatory and inflammation-resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.

Authors

David Meriwether, Dawoud Sulaiman, Carmen Volpe, Anna Dorfman, Victor Grijalva, Nasrin Dorreh, R. Sergio Solorzano-Vargas, Jifang Wang, Ellen O’Connor, Jeremy Papesh, Muriel Larauche, Hannah Trost, Mayakonda N. Palgunachari, G.M. Anantharamaiah, Harvey R. Herschman, Martin G. Martin, Alan M. Fogelman, Srinivasa T. Reddy

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Figure 5

4F treatment improves the inflammatory mediator profile of mouse macrophages.

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4F treatment improves the inflammatory mediator profile of mouse macroph...
*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (A–C) LPS-activated (25 ng/mL) BMDMs from FLOX and MKO mice were cotreated with D-4F (15 mg/mL) for 24 hours (n = 3/group). 4F significantly suppressed Il1b (A) and Tnf (B) expression in both FLOX and MKO BMDMs (fold change vs. 0 hours). LPS significantly increased prostanoid production in FLOX but not MKO mice, whereas 4F significantly reduced the levels of PGE2 (C) and PGD2 (D) in FLOX lysate from 10 hours. In FLOX lysate, 4F also selectively suppressed the COX pathway marker 11HETE without reducing the lipoxygenase product 15HETE (E). Statistical analyses were conducted as follows: (A, B) For each of the FLOX or MKO mice with or without 4F, 2-way ANOVA with Tukey’s multiple comparisons test and adjusted P values were used. (C, D) Three-way ANOVA with Tukey’s multiple comparisons test and adjusted P values were used. (E) For each of the 2 analytes, 2-way ANOVA with Tukey’s multiple comparisons test and adjusted P values were used.