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 10

Proposed pathogenic mechanisms of Cox2-MKO and CCHF-dependent intestinal inflammation together with the protective mechanisms of APOA1 mimetic peptides.

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Proposed pathogenic mechanisms of Cox2-MKO and CCHF-dependent intestinal...
(A) Cholate increases barrier permeability, initiating both bacteria and MyD88-dependent inflammation in Cox2-KO mice. Cox2-KO macrophages in the lamina propria exhibit an increased proinflammatory response to PAMP/LPS activation in response to PAMP/LPS activation, perhaps through loss of negative feedback control of NFκB. In turn, intestinal epithelium amplifies the proinflammatory stimuli of macrophages, resulting in a dysregulated proinflammatory positive feedback loop. Elevated oxPAPC levels further amplify the proinflammatory response. Loss of LXA4 production in Cox2-KO macrophages impairs the resolution of inflammation. The APOA1 mimetic peptide 4F interrupts the positive feedback loops by inhibiting the LPS-dependent activation of macrophages, blocking proinflammatory signal amplification by intestinal epithelium, and reducing the levels of oxPAPC while directly blocking their effects on macrophages. (B) Upon CCHF challenge, Cox2-MKO elevates lipid proinflammatory mediators in intestinal tissue and plasma while reducing proresolving mediators in tissue. 4F reduces the levels of proinflammatory LOX mediators in the cecum (right), possibly through direct clearance. 4F also reduces the levels of proinflammatory lipid mediators in plasma (left), possibly through enhancement of the TILT of lipoprotein-associated lipid inflammatory mediators into the lumen of the proximal small intestine (SI), in a manner comparable to the effect of 4F on the TICE of free cholesterol (FC) (17).