RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

Abstract

Hepatocyte cell death and liver inflammation have been well recognized as central characteristics of nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The kinase receptor-interacting protein 1 (RIP1) is a key regulator of apoptosis, necroptosis and inflammation, we thus hypothesized that the kinase activity of RIP1 may be involved in the pathogenesis of NASH. Wild-type and RIP1 kinase-dead (Rip1 K45A/K45A ) mice were fed with methionine-and choline-deficient diet (MCD) or high-fat diet (HFD) to establish distinct NASH models. In both models, compared to WT mice, Rip1 K45A/K45A mice exhibited significantly less liver injury, less steatosis, decreased inflammation, and less cell death in liver tissue. Moreover, hepatic fibrosis as characterized by Sirius Red staining, expression of α-SMA and other fibrosis markers, were significantly alleviated in Rip1 K45A/K45A mice than WT controls. Furthermore, using bone marrow transplantation to create chimeric mice, we found that it is the RIP1 kinase in hematopoietic-derived macrophages contributing mostly to the disease progression in NASH.Results from in vitro studies were in agreement with the in vivo data, demonstrating that RIP1 kinase was required for inflammasome activation and cell death induced by saturated fatty acid (palmitic acid) in bone marrow-derived macrophages (BMDMs). At last, we also found that the phosphorylation and expression of RIP1 was obviously increased in patients with NAFLD or NASH, but not in healthy controls. In summary, our results indicate that RIP1 kinase is activated during the pathogenesis of steatohepatitis, and consequently induces inflammation and cell death in macrophages, contributing to the disease progression. Our study suggests that macrophage RIP1 kinase represents a specific and potential target for the treatment of NASH.

RIP1 Perturbation Induces Chondrocyte Necroptosis and Promotes Osteoarthritis Pathogenesis via Targeting BMP7

“…Our findings indicate that upregulation of RIP1 is essentially involved in OA pathogenesis. Receptor-interacting protein kinase 1 has emerged as a crucial regulator in various human diseases such like cancers, neurodegeneration, autoimmune, and inflammatory diseases (Ofengeim and Yuan, 2013;Liu et al, 2015;Ofengeim et al, 2017;Wang et al, 2018;Tao et al, 2020). While the kinase activity of RIP1 mediates the activation of RIP3 and caspase-8 to promote necroptosis and apoptosis respectively, RIP1 also serves as a signaling scaffold to prevent the activation of RIP3 and caspase-8 in a kinase-independent manner, implying the tissue-specific complicated role of RIP1 (Degterev et al, 2019).…”

Roles of necroptosis in alcoholic liver disease and hepatic pathogenesis

“…In addition, further investigation indicated that the level of IL‐1β in mouse liver was closely consistent with the level of p‐MLKL in response to APAP exposure, as evidenced by co‐localization of p‐MLKL and IL‐1β 74 . Tao's study demonstrated that RIPK1 activity was promoted in hepatic macrophages after HFD feeding, but hepatic inflammation was obviously alleviated in RIPK1 kinase‐dead (RIPK1 K45A/K45A ) mice compared with WT mice, implying that RIPK1 is required for controlling hepatic macrophage infiltration and activation 75 . Also, the results obtained in both bone marrow–derived macrophages (BMDMs) and primary Kupffer cells (KCs) further confirmed the hypothesis that RIPK1 plays a crucial role in mediating inflammasome activity.…”

Liver Fibrosis—From Mechanisms of Injury to Modulation of Disease

“…′ kinase activity in hematopoietic-derived macrophages contributed mostly to the disease progression in NASH (31).…”

“…These protective effects were independent of a kinase activity, as RIPK1 K45A kinase dead knock in mice did not improve insulin resistance or reduce obesity on HFD feeding ( 30 ). However, Tao et al observed less liver injury, less steatosis and decreased inflammation in HFD- and MCD-fed RIPK1 K45A mice ( 31 ). Further investigations revealed that RIPK1′ kinase activity in hematopoietic-derived macrophages contributed mostly to the disease progression in NASH ( 31 ).…”

“…However, Tao et al observed less liver injury, less steatosis and decreased inflammation in HFD- and MCD-fed RIPK1 K45A mice ( 31 ). Further investigations revealed that RIPK1′ kinase activity in hematopoietic-derived macrophages contributed mostly to the disease progression in NASH ( 31 ).…”