IL-1-driven stromal cell response to Mycobacterium tuberculosis in mouse lungs

ABSTRACT: Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths a year. However, tuberculosis pathogenesis remains poorly understood and is not fully recapitulated in standard mouse models. Here we report that a comparison across three different susceptible mouse models identifies Mtb-induced gene signatures that predict active TB disease in humans significantly better than a signature from the standard C57BL/6 mouse model. Common to signatures from susceptible mice were myeloid cell response and immunosuppressive genes. In line with the signatures, an increase in lung myeloid cells, including neutrophils, was conserved across the susceptible mouse models, mimicking the neutrophilic inflammation observed in humans. Myeloid cells in the susceptible models and non-human primates exhibited high expression of immunosuppressive molecules including IL-1 receptor antagonist, which inhibits IL-1 signaling. Prior reports have suggested that excessive IL-1 signaling impairs Mtb control. By contrast, we found that enhancement of IL-1 signaling via deletion of IL-1 receptor antagonist promoted bacterial control in all three susceptible mouse models. IL-1 signaling enhanced cytokine production by lymphoid and stromal cells, suggesting a mechanism for IL-1 signaling in promoting Mtb control. Thus, we propose that myeloid cell expression of immunosuppressive molecules is a conserved mechanism exacerbating Mtb disease in mice, non-human primates, and humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE255213 | GEO | 2026/04/01

REPOSITORIES: GEO