Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model
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
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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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 3

APOA1 mimetics inhibit the development of intestinal inflammation in the Cox2-MKO and CCHF model of IBD.

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APOA1 mimetics inhibit the development of intestinal inflammation in the...
*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (A–F) Cox2-MKO (MKO) mice fed chow or CCHF for 7 and 10 weeks and treated with oral D-4F (500 μg/mL drinking water). (A) 4F significantly inhibited thickening of the ileo-ceco-colic junctions. (B) Representative images of MKO mice fed CHOW, CCHF, or CCHF + 4F for 10 weeks (left) (scale bars, 250 μm); 4F significantly inhibited the H&E disease score (0–12 points) (right). (C) 4F significantly reduced CCHF-dependent cecal muscularis thickening. (D–E) 4F treatment significantly reduced infiltration of macrophages (F4/80+) (D) and neutrophils (Ly6G+) (E) into the ileo-ceco-junctions of MKO mice on CCHF diet (left panels, representative images at 7 weeks; scale bars, 200 μm). (F) 4F significantly altered expression of Tnf and Il10 in the ileo-ceco-colic junctions of MKO mice fed CCHF for 7 weeks. (G–H) MKO mice fed CCHF for 10 weeks were treated with Tg6F for the full 10 weeks or the last 5 weeks. Both treatments significantly suppressed ileo-ceco-colic thickening (G) while also improving histopathology (H; representative images; scale bars, 200 μm). For A–C, and G we used 1-way ANOVA with Tukey’s multiple comparisons test and adjusted P values for statistical analyses. For D–F, we used Student’s t tests with Holm-Sidak correction for multiple tests and adjusted P values.