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.

Highlights

  • Annexin A1 (AnxA1) is an effector of the resolution of inflammation and is highly effective in terminating acute inflammatory responses

  • AnxA1 was expressed at low extent in livers of na€ıve mice, whereas both messenger RNA (mRNA) and protein content increased in a timedependent manner in livers of animals with nonalcoholic steatohepatitis (NASH) induced by feeding the methionine-choline deficient (MCD) diet (Fig. 1)

  • AnxA1 up-regulation paralleled the severity of NASH, an increased expression of AnxA1 was already evident along with early signs of inflammation in livers with only steatosis induced by feeding mice for 12 weeks with an high-fat diet (HFD) that caused obesity and insulin resistance (IR) (Supporting Fig. 2)

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Summary

Introduction

Annexin A1 (AnxA1) is an effector of the resolution of inflammation and is highly effective in terminating acute inflammatory responses. In MCD-fed WT mice, hepatic AnxA1 increased in parallel with progression of liver injury This mediator was detected in liver biopsies from patients with NASH and its degree of expression inversely correlated with the extent of fibrosis. Abbeviations: Abs, antibodies; ALT, alanine aminotransferase; ANOVA, analysis of variance; AnxA1; Annexin A1; CCL2, chemokine (C-C motif) ligand 2; CCR2, C-C chemokine receptor type 2; cDNA, complementary DNA; ELISA, enzyme-linked immunosorbent assay; FCM, flow cytometry; FPR2/ALX; formyl peptide receptor 2/lipoxin A4 receptor; H&E, hematoxilin and eosin; HFD, high-fat diet; hmf, high-magnification field; HSCs, hepatic stellate cells; IgG, immunoglobulin G; IHC, immunohistochemistry; IL, interleukin; iNOS, inducible nitric oxide synthase; IR, insulin resistance; KO, knockout; MCD; methionine-choline deficient; MetS, metabolic syndrome; MGL-1, macrophage galactose N-acetyl-galactosamine-specific lectin-1; MMP, matrix metalloproteinase; mRNA, messenger RNA; NAFLD; nonalcoholic fatty liver disease; NASH; nonalcoholic steatohepatitis; NO, nitric oxide; p38MAPK, p38 mitogen-activated protein kinase; RT-PCR, real-time polymerase chain reaction; a-SMA; alpha-smooth muscle actin; TGs, triglycerides; TGF-b1, transforming growth factor beta 1; TIMP-1, tissue inhibitor of metalloproteinase-1; TNF-a, tumor necrosis factor alpha; WT, wild type. It is increasingly evident that a failure in the mechanisms responsible for terminating inflammatory responses might result in chronic inflammation.[4]

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