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 9

4F treatment inhibits the development of colitis in the piroxicam-accelerated Il10–/– model of IBD.

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4F treatment inhibits the development of colitis in the piroxicam-accele...
*P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. (A–B) Il10–/– mice were treated with and without piroxicam (PX) and 4F (n = 4–7/group). (A) 4F partially rescued the effect of PX on colon length and colitis score. (B) 4F also improved disease histopathology: representative H&E images (scale bars, 200 μm) and H&E disease score are shown. Green bars indicate thickness of mucosa in Il10–/– + PX. Red arrows indicate inflammatory foci. (C) PX increased both whole intestinal barrier permeability of Il10–/– mice in a biphasic manner, as determined by LC-MS/MS of urinary excretion of sucralose (left), as well as the translocation of endotoxin into portal vein serum at day 9 (right). (D) 4F inhibited the production of prostanoids including PGE2 in LPS-activated Il10–/– BMDMs with or without PX (n = 3/group). (E–F) The lipid inflammatory mediator profile in the colons of the mice shown in A and B was determined by LC-MS/MS (see Supplemental Table 8) (n = 4–8 mice/group). (E) Heatmap of changes. (F) All significant differences are represented. 4F significantly inhibited the disease-dependent increase of proinflammatory LOX mediators. Tt, total. Statistical analyses were as follows: 1-way (A, B), repeated measures 1-way (C, left), or 3-way (D) ANOVA with Tukey’s multiple comparisons test and adjusted P values; Student’s t test (C, right). For E–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 and adjusted P values.