SAA1 Promotes Ulcerative Colitis and Activating Colonic TLR4/NF-κB/NLRP3 Signaling Pathway.

Abstract

Ulcerative colitis (UC) is a chronic inflammatory disease of the colorectal characterized by dysregulation of cytokine production resulting from abnormal innate and adaptive immune responses, which promote inflammation. Serum amyloid A (SAA) proteins are key components of the acute inflammatory response and have been found to be positively associated with UC disease activity in clinical studies. In this study, we employed a well-established DSS-induced UC model and conducted non-targeted proteomic detection to identify significantly differentially expressed proteins and related biological processes. Among these proteins, SAA1 was found to be significantly upregulated, showing functional enrichment in acute inflammatory pathways. Further investigation at both animal and cellular levels revealed that increased expression of SAA1 protein further enhanced the expression of pro-inflammatory cytokines such as IL-1β, TNF-α, IFN-γ, IL-6, IL-9, IL-17A, IL-17F and IL-22 while promoting the formation of an inflammatory microenvironment in the colon. Importantly, inhibition of SAA1 effectively alleviated pathological manifestations and tissue damage in UC by down-regulating cytokine expression. Mechanistically, our findings confirmed that SAA1 activates the TLR4/NF-kB signaling pathway and promotes NLRP3 inflammasome activation along with secretion of pro-inflammatory cytokines including TNF-a, IFN-γ, and IL-6. This ultimately leads to colonic microenvironment formation and progression of UC. Overall, our results highlight the critical involvement of SAA1 in UC progression as well as its potential utility as an inflammatory marker or therapeutic target.