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 8

4F can directly clear lipid proinflammatory mediators from intestinal tissue and plasma.

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4F can directly clear lipid proinflammatory mediators from intestinal ti...
*P < 0.05. (A) 4F fails to significantly suppress the disease-elevated inflammatory COX mediators in the intestinal tissue of Cox2-MKO (MKO) mice challenged for 8.5 weeks with CCHF, in contrast to its differential effect on disease-elevated inflammatory LOX mediators (see also Figure 4D). (B) Pairs of matching intestinal explants from MKO mice challenged for 8.5 weeks with CCHF (1 pair/mouse) were mounted in Ussing chambers. As determined by LC-MS/MS, lumen-side D-4F (50 mg/mL) significantly increased the pair-wise clearance of proinflammatory LOX mediators from the intestinal tissue into mucosal media. (C–D) Deuterated proinflammatory LOX mediators (15HETE-d, 12HETE-d, 13HODE-d) were combined with HDL and LDL (1 mg oxFA-d/[2.5 mg HDL + 5 mg LDL]) and added to the serosal sides of pairs of matching BL6 intestinal explants mounted in Ussing chambers. (C) There existed a baseline trans-intestinal transport of these tagged lipids (representative LC-MS/MS chromatogram). (D) Mucosal-side 4F (50 mg/mL) significantly increased the pair-wise trans-intestinal transport of both 13HODE-d and 15HETE-d (n = 3–6/group) For A, 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 (see also Figure 2). For B and D, we used Student’s t tests with Holm-Sidak correction for multiple tests and adjusted P values.