The role of Monocyte Chemoattractant Protein-Induced Protein-1 in the regulation of the immune responses to mycobacterial infection

Abstract

Abstract Mycobacterium tuberculosis (Mtb) infection is mainly controlled by protective cell-mediated immunity. TNFα and other mediators, such as nitric oxide (NO), are crucial to the macrophage’s antimicrobial activity. The RNA-binding protein MCPIP1 is a zinc-finger protein with RNase activity that targets the 3’UTR region of cytokine’s mRNA for degradation like IL-6, IL-1β, and IL-12. Here, we aim to investigate the role of MCPIP1 during infection and its contribution to Mtb’s immune evasion. Our observations show that MCPIP1 increases after Mtb infection, correlating with disease progression. Similarly, global MCPIP1 KO (MCPIP1 −/−) mice showed lower lung bacterial burden than WT mice after 30 days. To address wheater the reduced number of bacteria was due to the macrophage’s absent MCPIP1 expression, we generated myeloid-specific MCPIP1 KO mice (M-MCPIP1 −/−). M-MCPIP1 −/−mice showed a similar reduction of bacterial growth as the MCPIP1 −/−mice compared with their WT littermates. Infection of bone marrow-derived macrophages confirmed that myeloid-MCPIP1 deficient cells had improved control of bacterial growth with increased IL-1β, IL-6, IL-12, iNOS, and TNFα. To evidence the mechanism by which M-MCPIP1 −/−macrophages contribute to Mtb growth control, we blocked TNFα and iNOS activity. Results showed that protection in M-MCPIP1 −/−is partly due to these molecule’s high expression, as the blockade of these mediators increased the bacterial burden. Our preliminary data suggest that the induction of MCPIP1 contributes to the bacteria’s immune evasion by targeting critical anti-TB molecules. Further experiments are needed to understand the mechanisms involved and consider MCPIP1 as a target for host-directed therapy for TB. R21AI151936 R21AI171734