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 1

Dysregulated response to TLR-dependent signaling drives intestinal inflammation in the COX2-KO/CCHF models of IBD.

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Dysregulated response to TLR-dependent signaling drives intestinal infla...
*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (A) Mice treated with Cox2-TKO (upper panel) and BL6 + celecoxib (CX) (lower panel) develop transmural and sporadically ulcerating inflammation in their ileo-ceco-colic junctions when fed CCHF for 2 weeks (representative images). Scale bars: 250 μm. (B) C57BL/6J mice fed CCHF diet with or without CX were assessed at multiple time points (n = 4 mice/group/time point). CCHF significantly increased whole intestinal barrier permeability over the course of 0–7 days independently of CX (upper left panel). Endotoxin in portal vein serum significantly increased in both groups by 7 days (lower left panel). Inflammation significantly increased in CX-treated mice by 11 days (upper right panel), whereas epithelial damage did not significantly increase until day 14 (lower right panel) (histological assessments, 0–4 point scale). (C) Mice were pretreated with vancomycin, ampicillin, neomycin, and metroniadazole for 7 days and continued on antibiotics (AB) for 14 days of CCHF or CCHF + CX (n = 4/group). AB abrogated intestinal inflammation in mice treated with COX2-TKO (upper panel) and mice treated with C57BL6 + CX (BL6 + CX) (lower panel), as assessed by ileo-ceco-colic thickness. (D) Cox2-TKO and WT mice were treated 3 times per week i.p. with the MyD88 inhibitor T6167923 (0.25 mg/injection) over the course of 2 weeks on CCHF (n = 5/group). MyD88 inhibition (MyD88i) significantly inhibited intestinal inflammation in Cox2-TKO mice. (E) Cox2-MKO significantly enhanced RNA expression of Il1b (upper panel) and Tnf (lower panel) in LPS-activated BMDMs compared with FLOX controls (n = 3/group) (fold change vs. FLOX, 0 hours) (statistics shown only for FLOX vs. MKO). Two-way ANOVA and Tukey’s multiple comparisons test with adjusted P values were used for statistical analyses.