| Autor: |
Corleis, Björn, Tzouanas, Constantine N., Wadsworth II, Marc H., Cho, Josalyn L., Linder, Alice H., Schiff, Abigail E., Zessin, Björn, Stei, Fabian, Dorhoi, Anca, Dickey, Amy K., Medoff, Benjamin D., Shalek, Alex K., Kwon, Douglas S. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 12/6/2023, Vol. 15 Issue 725, p1-16, 16p |
| Abstrakt: |
Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to Mycobacterium tuberculosis (Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current and never smokers by performing single-cell RNA sequencing (scRNA-seq), flow cytometry, and functional assays. We observed the enrichment of immature inflammatory monocytes in the lungs of smokers compared with nonsmokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease. Using integrative scRNA-seq and flow cytometry, we identified CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provided evidence that the recruitment of monocytes into the lung was mediated by CCR2-binding chemokines, including CCL11. We also show that these cells exhibit elevated inflammatory responses upon exposure to Mtb and accelerated intracellular growth of Mtb compared with mature macrophages. This elevated Mtb growth could be inhibited by anti-inflammatory small molecules, providing a connection between smoking-induced pro-inflammatory states and permissiveness to Mtb growth. Our findings suggest a model in which smoking leads to the recruitment of immature inflammatory monocytes from the periphery to the lung, which results in the accumulation of these Mtb-permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to Mtb and identifies host-directed therapies to reduce the burden of TB among those who smoke. Editor's summary: It has been previously shown that tobacco smokers are at increased risk of developing active tuberculosis, but the underlying mechanism linking the two remains incompletely defined. Here, Corleis et al. identified a population of CD93-expressing inflammatory monocytes that are selectively recruited into the airspaces of individuals who smoke. The authors isolated these airspace monocytes from the bronchoalveolar lavage fluid of smokers or their precursors from blood and cultured them with Mycobacterium tuberculosis (Mtb), finding that the cells exhibited an exaggerated inflammatory response and more rapid intracellular Mtb growth as compared with mature macrophages from the same donors. Together, these data suggest that inflammatory airspace monocytes may mediate increased tuberculosis susceptibility among smokers and that host-directed therapies targeting these monocytes could prove an effective treatment strategy. —Courtney Malo [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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