Context-dependent transcriptional and epigenetic reprogramming shapes neutrophil antimicrobial and immunoregulatory functions in tuberculosis.

Authors

Cicero José Luíz Dos Ramos Almeida, Ricardo Cardoso Castro, Priscilla Mariane Cardoso-Silva, Fabiana Albani Zambuzi, Patrick Fernandes Silva, Veronica Soares Brauer, Humberto Dorigetto Gravina, Caroline Fontanari, Valdes Roberto Bollela, Fabiani Gai Frantz

Published in

Tuberculosis (Edinburgh, Scotland). Volume 160. Pages 102786. Jun 13, 2026. Epub Jun 13, 2026.

Abstract

Inflammatory microenvironments regulate immune cell differentiation, activation, and programming. Although traditionally considered terminally differentiated effectors, neutrophils can acquire distinct functional states in response to environmental cues. To examine context-dependent neutrophil programming, cells from healthy donors were cultured in vitro under cytokine regimens mimicking opposing inflammatory environments (GM-CSF/IFN-γ or IL-4/IL-13/TGF-β), alone or combined with PMA and Mycobacterium tuberculosis, to assess functional and transcriptional responses. GM-CSF/IFN-γ-conditioned neutrophils exhibited increased cell size, altered nuclear morphology, enhanced MHC class II and CD86 expression, and elevated IL-8 and reactive oxygen species production. This profile was associated with increased TNF-α, IL-10, TLR2, and TLR4 gene expression and reduced global DNA methylation. In contrast, IL-4/IL-13/TGF-β-conditioned neutrophils resembled non-conditioned controls regarding surface markers and cytokine production but showed reduced ROS generation and increased DNMT3A expression. Upon in vitro infection with M. tuberculosis, GM-CSF/IFN-γ-conditioned neutrophils produced higher IL-8 and IL-1β levels and formed more neutrophil extracellular traps. Additionally, plasma from patients with severe tuberculosis modulated TLR4, CCR7, and IP-10 expression in healthy neutrophils, indicating systemic inflammatory influences. These findings demonstrate that inflammatory conditioning induces coordinated transcriptional and epigenetic remodeling, shaping neutrophil antimicrobial and immunoregulatory potential in infectious contexts.

PMID:
42296595
Bibliographic data and abstract were imported from PubMed on 16 Jun 2026.

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