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 2

Cox2-MKO (MKO) mice challenged with CCHF exhibit elevated levels of lipid proinflammatory mediators in intestine and plasma, whereas the loss of inflammation-resolving LXA4 in intestine appears partially causal for disease in MKO mice fed CCHF.

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Cox2-MKO (MKO) mice challenged with CCHF exhibit elevated levels of lip...
*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (A–F) Lipid inflammatory mediators were determined by LC-MS/MS in the ileo-ceco-colic junctions (A) and plasmas (B) of MKO and FLOX mice fed CCHF or chow for 8.5 weeks (n = 5–7/group). All significant differences between MKO and FLOX on CCHF are presented: proinflammatory (Pro-INF) LOX and COX mediators in the intestines (C) and plasmas (D); PGE2, PGD2, and associated metabolites in both intestine (Int) and plasma (Pl) (E). Tt, total. In intestine, Cox2-MKO significantly reduced the levels of both the specialized proresolving mediator (SPM) LXA4 and total 5LOX SPM, together with the ratio of total 5LOX SPM to LTB4 + 6trans12epiLTB4 (Tt LTB4) (F). (G) A stable analog of LXA4 (BML111) administered twice weekly i.p. significantly inhibited markers of disease including ileo-ceco-colic thickness (n = 10/group) (left) and H&E score (n = 3–5/group) (right). For A–F, we used the Benjamini-Hochberg procedure applied to 1-way ANOVA for each lipidomic analyte with FDR at level α = 0.05, followed by Tukey’s multiple comparisons test with adjusted P values for statistical analyses. For G, we used a 1-way ANOVA with Tukey’s multiple comparisons test and adjusted P values.