Macrophage RIPK3 facilitates TRAF6 K63-linked ubiquitination and exacerbates acute pancreatitis

Abstract

Abstract Acute pancreatitis (AP) is characterized by acinar cell injury and death triggered by multiple etiologies, culminating in local and systemic inflammatory responses. Current therapeutic options for AP, particularly severe AP, remain limited. While RIPK3-mediated necroptosis in pancreatic acinar cells has been implicated in AP pathogenesis, here we uncover an indispensable role for macrophage RIPK3 in driving AP-associated inflammation. We find that RIPK3 expression is progressively upregulated during AP progression. In cerulein-induced AP, both pharmacological RIPK3 inhibition and macrophage-specific Ripk3 deletion attenuate pancreatic injury, whereas Mlkl deletion in macrophages has no effect. Macrophage-specific RIPK3 knockout also reduces systemic inflammation and improves survival in the severe AP (NaTc-SAP) mouse model. After LPS activation, RIPK3-deficient macrophages exhibit impaired inflammatory responses and reduced NF-κB and MAPK activation. Mechanistically, RIPK3 interacts with TRAF6 to promote its K63-linked ubiquitination. These findings establish macrophage RIPK3 as a key mediator of AP and highlight its potential as a therapeutic target.