Therapeutic intervention with anti-complement component 5 antibody does not reduce nash but does attenuate atherosclerosis and mif concentrations in ldlr-/-.Leiden mice

Seidel, Florine, Kleemann, Robert, van Duyvenvoorde, Wim, van Trigt, Nikki, Keijzer, Nanda, van der Kooij, Sandra, van Kooten, Cees, Verschuren, Lars, Menke, Aswin, Kiliaan, Amanda J., Winter, Johnathan, Hughes, Timothy R. ORCID: https://orcid.org/0000-0003-2348-3490, Morgan, B. Paul, Baas, Frank, Fluiter, Kees and Morrison, Martine C. 2022. Therapeutic intervention with anti-complement component 5 antibody does not reduce nash but does attenuate atherosclerosis and mif concentrations in ldlr-/-.Leiden mice. International Journal of Molecular Sciences 23 (18) , 10736. 10.3390/ijms231810736

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Abstract

Background: Chronic inflammation is an important driver in the progression of nonalcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains unclear. Methods: After 20 weeks of high-fat diet (HFD) feeding, obese Ldlr-/-.Leiden mice were treated twice a week with an established anti-C5 antibody (BB5.1) or vehicle control. A separate group of mice was kept on a chow diet as a healthy reference. After 12 weeks of treatment, NASH was analyzed histopathologically, and genome-wide hepatic gene expression was analyzed by next-generation sequencing and pathway analysis. Atherosclerotic lesion area and severity were quantified histopathologically in the aortic roots. Results: Anti-C5 treatment considerably reduced complement system activity in plasma and MAC deposition in the liver but did not affect NASH. Anti-C5 did, however, reduce the development of atherosclerosis, limiting the total lesion size and severity independently of an effect on plasma cholesterol but with reductions in oxidized LDL (oxLDL) and macrophage migration inhibitory factor (MIF). Conclusion: We show, for the first time, that treatment with an anti-C5 antibody in advanced stages of NASH is not sufficient to reduce the disease, while therapeutic intervention against established atherosclerosis is beneficial to limit further progression.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	MDPI
ISSN:	1422-0067
Date of First Compliant Deposit:	30 November 2022
Date of Acceptance:	10 September 2022
Last Modified:	07 May 2023 14:31
URI:	https://orca.cardiff.ac.uk/id/eprint/154574

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