The regulatory roles of DUSP6 in innate immune response against Yersinia Tuberculosis 2850

Abstract Description Mitogen-activated protein kinases (MAPKs) including ERK, JNK and p38 play important roles in immune responses. Dual-specificity phosphatases (DUSPs) serve as primary negative regulators of MAPKs. The aim of this project is to investigate the regulatory role of DUSP6 in innate immunity. In response to both LPS stimulation and Yersinia Tuberculosis (Yptb) infection, increased ERK phosphorylation but reduced p38 and JNK phosphorylation was detected in DUSP6 KO bone marrow-derived macrophages (BMDMs) compared to that in WT BMDMs. The production of IL-6 and TNF-α was found to be decreased in DUSP6 KO BMDMs. Interestingly, IFN-β expression is also lower in KO BMDMs, which was associated with reduced TBK1 and IRF3 phosphorylation. Upon Yptb infection, DUSP6 KO mice developed more severe disease than WT mice with higher bacterial load and stronger inflammation associated with higher level of neutrophil in both the liver and spleen. Meanwhile, the level of IFN-β in liver homogenate was found to be lower in KO mice compared to WT. Bulk RNA sequencing of BMDMs post-Yptb infection indicated downregulation of innate immune pathways and upregulation of the ubiquitination pathway in KO group, suggesting that DUSP6 may regulate innate immune pathways through regulating the stability of important molecules associated with the production of type I IFN, which requires further investigation. Funding Sources This project is supported by NMRC. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)