Macrophage-specific iPla₂β deletion worsens hepatic inflammation in MCD-induced NASH by increasing M1/M2 activation.

Background Polymorphisms of iPLA₂β are associated with an increase of serum C-reactive protein suggesting its role in inflammation. It is known that iPla₂β regulates monocyte differentiation and monocyte migration to sites of inflammation, however, its role in NASH is still elusive. We previously reported that female iPla₂β-null mice fed with methionine- and choline-deficient diet (MCDD) displayed opposing phenotypes; on one hand attenuation of liver enzymes and liver fatty acids but on the other hand exacerbation of liver fibrosis (BBA 2019, 1864, 677). Here, we examined whether macrophage-specific iPla₂β deletion has any effects on NASH induced by MCDD.

Methods Macrophage-specific (lysM-Cre) iPla₂β-deficient (KO) mice with exon 6-8 deletion were generated. Female WT or iPla₂β ^flox/flox were used as controls. KO mice were fed with chow or MCD for 3.5 weeks. Livers were harvested for RT-PCR analysis. Blood and liver lipids were analyzed.

Results MCDD-fed control mice induced hepatic steatosis as observed by an increase of liver lipids. MCDD-fed KO mice showed a further increase of hepatic triglycerides (TG) without altering serum TG, phospholipids, and free fatty acid levels. MCD feeding caused a severe reduction of body weights and an increase of normalized liver weights in both controls and KO. Under MCD feeding, KO showed a further elevation of hepatic inflammation as observed by mRNA expression of F4/80, Ly6C, CD68, CD11b, MCP1, CCL3, VCAM1, and ICAM1 as well as M1 markers TNF-α and IL-6. In control mice, MCDD feeding increased mRNA expression of M2 markers including arginase-1 and chitinase-like 3, and interestingly, these markers were further increased by the deficiency. Moreover, iPla₂β deficiency further increased hepatic fibrosis as measured by collagen1-alpha, plasminogen activator inhibitor-1, and tissue inhibitor of metalloproteinases-1 mRNA expression.

Conclusions Under MCDD, iPla₂β-null mice showed an increase of liver fibrosis without altering liver inflammation, while macrophage-specific iPla₂β deletion enhanced liver fibrosis and inflammation. Thus, iPla₂β deficiency in other cell types may play a protective role in global deficiency. In addition to M1, macrophage iPla₂β deficiency increased M2 phenotypes rendering susceptibility to MCDD-induced lean NASH. Our study presents novel findings revealing a protective role of iPla₂β in macrophages, particularly regarding M2 activation, during chronic liver diseases such as NASH.