Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis

Abstract

The fundamental mechanism how heterogeneous hepatic macrophage (Mφ) subsets fulfill diverse functions in health and disease has not been elucidated. We recently reported that CCR9+ inflammatory Mφs play a critical role in the course of acute liver injury. To clarify the origin and differentiation of CCR9+Mφs, we used a unique partial bone marrow (BM) chimera model with liver shielding for maintaining hepatic resident Mφs. First, irradiated mice developed less liver injury with less Mφs accumulation by Concanavalin A (Con A) regardless of liver shielding. In mice receiving further BM transplantation, CD11blowF4/80high hepatic-resident Mφs were not replaced by transplanted donors under steady state, while under inflammatory state by Con A, CCR9+Mφs were firmly replaced by donors, indicating that CCR9+Mφs originate from BM, but not from hepatic-resident cells. Regarding the mechanism of differentiation and proliferation, EdU+CCR9+Mφs with a proliferative potential were detected specifically in the inflamed liver, and in vitro study revealed that BM-derived CD11b+ cells co-cultured with hepatic stellate cells (HSCs) or stimulated with retinoic acids could acquire CCR9 with antigen-presenting ability. Collectively, our study demonstrates that inflammatory Mφs originate from BM and became locally differentiated and proliferated by interaction with HSCs via CCR9 axis during acute liver injury.

Intestinal barrier regulates immune responses in the liver via IL-10–producing macrophages

“…) macrophages play a critical role in Con A-induced acute liver injury by inducing Th1 responses (16,17). Consistently, CCR9 expression in DW-Con A macrophages was significantly elevated, whereas DSS-Con A macrophages lacked CCR9 expression.…”

“…We recently reported the critical role of TNF-α-producing CCR9 + CD11b + macrophages in the pathogenesis of Con A-induced hepatitis (16,17). These macrophages are characterized as classically activated macrophages that contribute to host defenses against a variety of bacteria and viruses and play a substantial role in antitumor immunity.…”

RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis

“…However, splenectomy in WT mice did not attenuate ConA hepatitis at 24 h, suggesting that the spleen by itself is not responsible for the severity of the disease. Consistent with this, splenectomy 2 weeks before ConA treatment did not affect liver injury induced by ConA treatment [28]. However, ALT levels in splenectomized Ramp1 −/− mice fell by 50% at 24 h after ConA treatment when compared with those in sham-operated Ramp1 −/− mice, suggesting that RAMP1 signaling in splenocytes improves ConA-mediated hepatitis.…”

Liver Fibrosis Markers Improve Prediction of Outcome in Non‐Acetaminophen‐Associated Acute Liver Failure

“…( ) HSCs relay inflammatory signals ( ) ; they have also been shown to participate in inflammatory macrophage differentiation and local proliferation in a murine concanavalin A acute liver injury model. ( ) Using a murine tetrachloride liver fibrosis model, Issa et al ( ) showed that a mutation in collagen‐I that confers resistance to collagenase degradation resulted in diminished stellate cell apoptosis and impaired hepatocyte regeneration. Activated HSCs participate in the termination of hepatocyte regeneration, probably through the elevated expression of transforming growth factor β, a well‐known hepatocyte antiproliferative factor, as demonstrated in various murine models of liver fibrosis.…”