How is the inflammatory response regulated to prevent tissue damage? This study elucidates the role of the TRIF-RIPK1-Caspase-8 signaling pathway in modulating TLR4-driven gene expression in macrophages. Results demonstrate that the TRIF-RIPK1-Caspase-8 complex is essential for LPS-induced CYLD degradation, with TRIF functioning upstream of RIPK1. The homotypic interaction motif of TRIF and the death domain of RIPK1 are crucial for Caspase-8 activation, which then cleaves CYLD. Furthermore, cFLIP interacts with Caspase-8 to modulate its protease activity on CYLD and cell death. These findings reveal the opposite roles of TRIF-Caspase-8 and CYLD in regulating TLR4 signaling.
In line with the focus of Immunology on understanding immune mechanisms and responses, this paper explores the intricate TRIF-RIPK1-Caspase-8 signaling pathway in regulating inflammatory cytokine expression, offering insights into the regulatory processes that maintain immune homeostasis and prevent excessive inflammation, a key area of investigation within the journal.