The following is a summary of “Human Alveolar and Monocyte-Derived Human Macrophage Responses to Mycobacterium tuberculosis,” published in the June 2024 issue of Allergy & Immunology by Campo, et al.
Alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) play crucial roles in the early lung immune responses to Mycobacterium tuberculosis. Understanding the differences in the responses of these distinct macrophage types is essential for elucidating the mechanisms of tuberculosis pathogenesis.
For a study, researchers sought to investigate whether M. tuberculosis triggers distinct and critical antimicrobial pathways in human AMs compared to MDMs.
Paired human AMs and 5-day MCSF-derived MDMs were obtained from 6 healthy volunteers. The cells were infected with M. tuberculosis H37Rv for 6 hours, RNA was isolated, and transcriptomic profiles were analyzed using RNA sequencing. Differentially expressed genes (DEGs) were identified and gene set enrichment analysis was performed to compare the responses between AMs and MDMs.
In response to M. tuberculosis infection, 681 genes were differentially expressed in AMs compared to MDMs, while 4,538 genes were differentially expressed in MDMs but not AMs (FDR< 0.05). Gene set enrichment analysis revealed that type I and II IFN response pathways were selectively induced in M. tuberculosis-infected AMs (FDR< 0.05). Gene sets related to MYC targets, unfolded protein response, and MTORC1 signaling were selectively enriched in MDMs (FDR< 0.05). IFNA1, IFNA8, IFNE, and IFNL1 were significantly upregulated in AMs at baseline and/or after M. tuberculosis infection. Specifically, IFNA8 modulated M. tuberculosis-induced proinflammatory cytokines and stimulated unique transcriptomes compared to other interferons. Several DNA sensors and IFN regulatory factors exhibited higher expression in AMs at baseline and/or following M. tuberculosis infection.
M.tuberculosis infection induces distinct transcriptional responses in human AMs compared to MDMs. It included the upregulation of the IFN response pathway and specific DNA sensors in AMs, highlighting unique and essential antimicrobial pathways that may be critical for tuberculosis pathogenesis.
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