MicroRNA 26a (miR-26a)/KLF4 and CREB-C/EBPβ regulate innate immune signaling, the polarization of macrophages and the trafficking of Mycobacterium tuberculosis to lysosomes during infection

PLoS Pathogens

Sohini Chakraborty¹  Zhumur Ghosh¹  Sanjaya Kumar Sahu²  Manish Kumar²  Joyoti Basu²  Manikuntala Kundu²  Srijon Kaushik Banerjee²  Ranjeet Kumar²  Kuladip Jana³  Pushpa Gupta⁴  Umesh D. Gupta⁴ 

[1] Bioinformatics Centre, Bose Institute, Kolkata, India;Department of Chemistry, Bose Institute, Kolkata, India;Division of Molecular Medicine, Bose Institute, Kolkata, India;National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Tajganj, Agra, India

关键词: Mycobacterium tuberculosis;    Macrophages;    Autophagic cell death;    MicroRNAs;    Small interfering RNAs;    Transcriptional control;    Transcription factors;    Lysosomes;   

DOI  :  10.1371/journal.ppat.1006410

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

For efficient clearance of Mycobacterium tuberculosis (Mtb), macrophages tilt towards M1 polarization leading to the activation of transcription factors associated with the production of antibacterial effector molecules such as nitric oxide (NO) and proinflammatory cytokines such as interleukin 1 β (IL-1β) and tumor necrosis factor α (TNF-α). At the same time, resolution of inflammation is associated with M2 polarization with increased production of arginase and cytokines such as IL-10. The transcriptional and post-transcriptional mechanisms that govern the balance between M1 and M2 polarization, and bacteria-containing processes such as autophagy and trafficking of Mtb to lysosomes, are incompletely understood. Here we report for the first time, that the transcription factor KLF4 is targeted by microRNA-26a (miR-26a). During Mtb infection, downregulation of miR-26a (observed both ex vivo and in vivo) facilitates upregulation of KLF4 which in turn favors increased arginase and decreased iNOS activity. We further demonstrate that KLF4 prevents trafficking of Mtb to lysosomes. The CREB-C/EBPβ signaling axis also favors M2 polarization. Downregulation of miR-26a and upregulation of C/ebpbeta were observed both in infected macrophages as well as in infected mice. Knockdown of C/ebpbeta repressed the expression of selected M2 markers such as Il10 and Irf4 in infected macrophages. The importance of these pathways is substantiated by observations that expression of miR-26a mimic or knockdown of Klf4 or Creb or C/ebpbeta, attenuated the survival of Mtb in macrophages. Taken together, our results attribute crucial roles for the miR-26a/KLF4 and CREB-C/EBPβsignaling pathways in regulating the survival of Mtb in macrophages. These studies expand our understanding of how Mtb hijacks host signaling pathways to survive in macrophages, and open up new exploratory avenues for host-targeted interventions.

【 授权许可】

CC BY