The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner. NLRP3-inhibition by geniposidic acid (GPA), a novel NLRP3-specific covalent inhibitor that directly interacts with NLRP3, in hepatocytes and macrophages abated BA-induced inflammation. Moreover, NLRP3-deletion or its inhibition mitigated ANIT-induced cholestatic inflammation, whereas disrupting the crosstalk between hepatic macrophages and hepatocytes attenuated the hepatoprotective effect of GPA against ANIT-induced cholestatic inflammation. Therefore, blocking this crosstalk by suppressing NLRP3 inflammasome activation may represent a novel therapeutic strategy for cholestasis.

Platelet factor 4 (PF4), also referred to as CXCL4, is a significant component of the C-X-C chemokine family, predominantly localized within the alpha granules of platelets. It is recognized for its anti-heparin and anti-angiogenic properties. However, the involvement of PF4 in inflammatory processes has not been extensively investigated. This article aims to explore the diverse functions of PF4 in the context of inflammatory diseases, emphasizing its potential dual regulatory roles across various immune cell types and pathological conditions. Recent research has enhanced our comprehension of PF4, revealing its production not only in platelets but also in macrophages and activated T cells, thereby extending its functional repertoire beyond its conventional roles. Consequently, this review provides a thorough analysis of PF4’s influence on inflammatory diseases and offers perspectives and recommendations for future research endeavors.