BHLHE40 Regulates Myeloid Cell Polarization through IL-10–Dependent and –Independent Mechanisms

Skyler V. Hendrix, Yassin Mreyoud, Michael E. McNehlan, Asya Smirnov, Sthefany M. Chavez, Brian Hie, Megan M. Chamberland, Tara R. Bradstreet, Ashlee M. Webber, Darren Kreamalmeyer, Reshma Taneja, Bryan D. Bryson, Brian T. Edelson, Christina L. Stallings

Research output: Contribution to journalArticlepeer-review


Better understanding of the host responses to Mycobacterium tuberculosis infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling M. tuberculosis infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40−/− mice to M. tuberculosis infection. Deletion of Bhlhe40 in lung macrophages and dendritic cells is sufficient to increase the susceptibility of mice to M. tuberculosis infection, but how BHLHE40 impacts macrophage and dendritic cell responses to M. tuberculosis is unknown. In this study, we report that BHLHE40 is required in myeloid cells exposed to GM-CSF, an abundant cytokine in the lung, to promote the expression of genes associated with a proinflammatory state and better control of M. tuberculosis infection. Loss of Bhlhe40 expression in murine bone marrow–derived myeloid cells cultured in the presence of GM-CSF results in lower levels of proinflammatory associated signaling molecules IL-1b, IL-6, IL-12, TNF-a, inducible NO synthase, IL-2, KC, and RANTES, as well as higher levels of the anti-inflammatory–associated molecules MCP-1 and IL-10 following exposure to heat-killed M. tuberculosis. Deletion of Il10 in Bhlhe402/2 myeloid cells restored some, but not all, proinflammatory signals, demonstrating that BHLHE40 promotes proinflammatory responses via both IL-10–dependent and –independent mechanisms. In addition, we show that macrophages and neutrophils within the lungs of M. tuberculosis–infected Bhlhe402/2 mice exhibit defects in inducible NO synthase production compared with infected wild-type mice, supporting that BHLHE40 promotes proinflammatory responses in innate immune cells, which may contribute to the essential role for BHLHE40 during M. tuberculosis infection in vivo.

Original languageEnglish
Pages (from-to)1766-1781
Number of pages16
JournalJournal of Immunology
Issue number11
StatePublished - Jun 1 2024


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