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 September 3, 2019; First published June 11, 2019
Citation Information: J Clin Invest. 2019;129(9):3670-3685. https://doi.org/10.1172/JCI123700.
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Categories: 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 7

Oxidized PAPC is elevated in the plasma and ceca of Cox2-MKO and CCHF-fed mice, whereas 4F both reduces oxidized PAPC in vivo and inhibits oxidized PAPC-dependent proinflammatory response in human macrophages.

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Oxidized PAPC is elevated in the plasma and ceca of Cox2-MKO and CCHF-fe...
*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Levels of oxPAPC products (POVPC, PGPC, and KOdiAPC) were determined in the ceca (n = 7) (A) and plasmas (n = 10) (B) of Cox2-MKO (MKO) and FLOX mice fed CCHF or chow for 8.5 weeks. Independently, the effect of 4F on oxPAPC in the ceca (C) and plasma (D) of MKO and FLOX mice fed CCHF for 3 weeks was determined. Last, human THP-1 macrophages were treated with 1 μM POVPC for 3 hours with and without the apoA-I mimetic peptides 4F and 3F(14); and expression of IL1B was determined by qPCR (n = 3–6) (fold change vs. NT) (E) After 8.5 weeks, MKO + CCHF diet significantly increased oxPAPC species in both ceca and plasma. 4F significantly lowered levels of oxPAPC in vivo, and 4F but not 3F(14) significantly inhibited the proinflammatory effect of POVPC on macrophages. For each analyte in A–D, 2-way ANOVA with Tukey’s multiple comparisons test and adjusted P values was used. A 1-way ANOVA with Tukey’s multiple comparisons test and adjusted P values was used for E.