Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis

Authors

Arshad Khan
Kangling Zhang
Vipul K. Singh
Abhishek Mishra
Priyanka Kachroo
Tian Bing
Jong Hak Won
Eder Ledezma-Campos
Genesis P. Aguillón-Durán, Secretaria de Salud de Tamaulipas
Blanca I. Restrepo, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

5-19-2022

Abstract

Mycobacterium tuberculosis (Mtb) is responsible for approximately 1.5 million deaths each year. Though 10% of patients develop tuberculosis (TB) after infection, 90% of these infections are latent. Further, mice are nearly uniformly susceptible to Mtb but their M1-polarized macrophages (M1-MΦs) can inhibit Mtb in vitro, suggesting that M1-MΦs may be able to regulate anti-TB immunity. We sought to determine whether human MΦ heterogeneity contributes to TB immunity. Here we show that IFN-γ-programmed M1-MΦs degrade Mtb through increased expression of innate immunity regulatory genes (Inregs). In contrast, IL-4-programmed M2-polarized MΦs (M2-MΦs) are permissive for Mtb proliferation and exhibit reduced Inregs expression. M1-MΦs and M2-MΦs express pro- and anti-inflammatory cytokine-chemokines, respectively, and M1-MΦs show nitric oxide and autophagy-dependent degradation of Mtb, leading to increased antigen presentation to T cells through an ATG-RAB7-cathepsin pathway. Despite Mtb infection, M1-MΦs show increased histone acetylation at the ATG5 promoter and pro-autophagy phenotypes, while increased histone deacetylases lead to decreased autophagy in M2-MΦs. Finally, Mtb-infected neonatal macaques express human Inregs in their lymph nodes and macrophages, suggesting that M1 and M2 phenotypes can mediate immunity to TB in both humans and macaques. We conclude that human MФ subsets show unique patterns of gene expression that enable differential control of TB after infection. These genes could serve as targets for diagnosis and immunotherapy of TB.

Comments

Copyright © 2022, The Author(s)

Recommended Citation

Khan, A., Zhang, K., Singh, V.K. et al. Human M1 macrophages express unique innate immune response genes after mycobacterial infection to defend against tuberculosis. Commun Biol 5, 480 (2022). https://doi.org/10.1038/s42003-022-03387-9

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Communications Biology

DOI

10.1038/s42003-022-03387-9

Academic Level

faculty

Mentor/PI Department

Office of Human Genetics