ABSTRACT
Background
Sterile alpha and TIR motif-containing 1 (Sarm1) is known as a negative regulator of inflammatory responses. However, its role in inflammatory bowel disease (IBD) is still unclear.
Objective
This study aimed to explore the function of Sarm1 in IBD and its underlying mechanisms. Sarm1 and tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) knockout (KO) micewere established.
Methods
The colitis was induced using dextran sulfate sodium (DSS). Bone marrow-derived macrophages (BMDMs) were isolated and stimulated with lipopolysaccharides (LPS) or cytidine phosphate guanosine(CpG). Inflammatory cytokines were measured viaELISA. qPCR and Western blotting were used to determine the levels of the mRNA and protein expression, respectively.
Results
It was demonstrated that reduced expression of Sarm1 was correlated with the severity of IBD in ulcerative colitis patients, and also with the reduction of pro-inflammatory cytokines in the mouse model induced by DSS. It was further observed that Sarm1 KO enhanced the induction of pro-inflammatory cytokines in both animal and in vitro cell models. Sarm1 deficiency in macrophages increased the severity of colitis in the mouse model induced by DSS. Moreover, Sarm1 regulatedTRAF3 recruitment to myeloid differentiation primary response protein 88 (MyD88), which in turn controlled the MYD88-mediated inflammatory responses.
Conclusions
In summary, our data suggest that Sarm1 controls the MYD88-mediated inflammatory responses in IBD via its regulation of TRAF3 recruitment.
KEY POINTS
1. Sarm1 KO enhances the induction of pro-inflammatory cytokines in both animal and in vitro cell models.
2. Sarm1 deficiency in macrophages increases the severity of colitis in the mouse model.
3. Sarm1 regulates TRAF3 recruitment to MyD88.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
Data curation: Huijuan Fan, Chun Song and Jingyu Zhang; Project administration: Huijuan Fan and Jingyu Zhang; Supervision: Huijuan Fan and Jingyu Zhang; Writing – original draft: Huijuan Fan and Jingyu Zhang; Writing – review and editing: Huijuan Fan and Jingyu Zhang.
Data availability statement
The data used to support the findings of this study are available from the corresponding author upon request.
Ethical approval
All animal experiments were conducted in strict accordance with protocols approved by the Ethics Committee of the Second Affiliated Hospital, Air Force Medical University (#2023.036.g2).