Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice

Abstract

Annexin A1 (AnxA1) is an effector of the resolution of inflammation and is highly effective in terminating acute inflammatory responses. However, its role in chronic settings is less investigated. Because changes in AnxA1 expression within adipose tissue characterize obesity in mice and humans, we queried a possible role for AnxA1 in the pathogenesis of nonalcoholic steatohepatitis (NASH), a disease commonly associated with obesity. NASH was induced in wild-type (WT) and AnxA1 knockout (AnxA1 KO) C57BL/6 mice by feeding a methionine-choline deficient (MCD) diet up to 8 weeks. In MCD-fed WT mice, hepatic AnxA1 increased in parallel with progression of liver injury. This mediator was also detected in liver biopsies from patients with NASH and its degree of expression inversely correlated with the extent of fibrosis. In both humans and rodents, AnxA1 production was selectively localized in liver macrophages. NASH in AnxA1 KO mice was characterized by enhanced lobular inflammation resulting from increased macrophage recruitment and exacerbation of the M1 phenotype. Consistently, in vitro addition of recombinant AnxA1 to macrophages isolated from NASH livers down-modulated M1 polarization through stimulation of interleukin-10 production. Furthermore, the degree of hepatic fibrosis was enhanced in MCD-fed AnxA1 KO mice, an effect associated with augmented liver production of the profibrotic lectin, galectin-3. Accordingly, AnxA1 addition to isolated hepatic macrophages reduced galectin-3 expression. Conclusions: Macrophage-derived AnxA1 plays a functional role in modulating hepatic inflammation and fibrogenesis during NASH progression, suggesting the possible use of AnxA1 analogs for therapeutic control of this disease.

Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes

“…*p < 0.05 cardiomyopathy and nephropathy. Previously, both full-length AXNA1 and the Ac2-26 peptide (the N-terminal functional fragment of ANXA1) have been used in vivo and both elicit biological function [17][18][19]). In this study, we chose to use fulllength hrANXA1, as the dose of full-length ANXA1 needed to induce biological function is up to 20 times less than that of the Ac2-26 peptide [36] and 14 times less than that needed to induce changes in gene expression in terms of molarity [37].…”

“…ANXA1 levels are modulated in many disease states including cancer [13], multiple sclerosis [14], cystic fibrosis [15] and obesity/the metabolic syndrome [16]. Human recombinant ANXA1 (hrANXA1) or its N-terminal peptide (Ac2-26) have therapeutic benefits in many experimental models of disease, including rheumatoid arthritis [17], atherosclerosis [18] and nonalcoholic steatohepatitis [19].…”

Annexins – insights from knockout mice

“…To date, administration of the AnxA1 derived N-terminal Ac2-26 peptide is the most common approach (D'Acquisto et al, 2008;Perretti and D'Acquisto, 2009;Perretti and Dalli, 2009;Gavins and Hickey, 2012;Yang et al, 2013a;Locatelli et al, 2014;Sugimoto et al, 2016). Overall, exogenous administration of AnxA1 or AnxA1-derived peptides are effective to limit or resolve inflammation in a large range of disease models in rodents, including stroke, myocardial ischemia, non-alcoholic steatohepatitis, rheumatoid arthritis, multiple sclerosis, colitis and asthma.…”

The role of lipoxins in cardiometabolic physiology and disease

“…The ω3-PUFA-derived SPMs attenuate obesity-induced adipose inflammation and related liver disease [54][55][56][57][58] as well as many features of CVD (for review articles, see [22,40,59,60]). Similarly, AnxA1 correlates with reduced adipose inflammation and protects against nonalcoholic steatohepatitis [61,62]. Furthermore, AnxA1 may protect against myocardial infarction [63] and when using collagen IV-targeted nanoparticles to deliver Ac2-26 (the N-terminal derived peptide of AnxA1) to the advanced atherosclerotic lesions of fat-fed Ldlr − / − mice, Ac2-26 promotes plaque stability while decreasing oxidative stress and plaque necrosis [64].…”