Bacillus Calmette–Guérin–induced interleukin‐10 inhibits S100A8/A9 production and hinders development of T helper type 1 memory in mice

Wang, Yaping; Sun, Youhong; Zheng, Yong; Yang, Yunxia; He, Lingjuan; Qu, Peijie; Zhou, Fangting; Xu, XiaoXu; Bai, Xuanchang; Chen, Xin; Yuan, Yangxuan; Liu, Min; Pan, Qin

doi:10.1002/eji.202250204

Cited by 4 publications

(1 citation statement)

References 45 publications

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“…This reduction in CCR2 expression is mediated by IFNγ-induced mRNA instability, potentially serving to retain monocytes at the site of recruitment and dampen a positive feedback loop 22 . Similarly, BCG has been shown in other contexts to reduce the expression of S100A8 and S100A9, two calcium-binding proteins that can heterodimerize and stimulate IFNγ production in CD4+ T-cells via an IL-10 dependent mechanism 23 . By suppressing their activity, runaway signaling and exhaustion is avoided.…”

Section: Resultsmentioning

confidence: 98%

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

Solomon,

Ben-Moshe,

Hoffman

et al. 2024

Preprint

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Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette-Guerin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium (S.Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

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Section: Resultsmentioning

confidence: 98%

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

Solomon,

Ben-Moshe,

Hoffman

et al. 2024

Preprint

View full text Add to dashboard Cite

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Helper T cell bias following tuberculosis chemotherapy identifies opportunities for therapeutic vaccination to prevent relapse

Martinez-Martinez,

Huante,

Chauhan

et al. 2023

npj Vaccines

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Therapeutic vaccines have promise as adjunctive treatment for tuberculosis (TB) or as preventives against TB relapse. An important development challenge is the limited understanding of T helper (Th) cell roles during these stages of disease. A murine model of TB relapse was used to identify changes in Th populations and cytokine microenvironment. Active TB promoted expansion of Th1, Th2, Th17, and Th22 cells and cytokines in the lung. Following drug therapy, pulmonary Th17 and Th22 cells contracted, Th1 cells remained elevated, while Th cells producing IL-4 or IL-10 expanded. At relapse, Th22 cells failed to re-expand in the lung despite a moderate re-expansion of Th1 and Th17 cells and an increase in Th cytokine polyfunctionality. The dynamics of Th populations further differed by tissue compartment and disease presentation. These outcomes identify immune bias by Th subpopulations during TB relapse as candidate mechanisms for pathogenesis and targets for therapeutic vaccination.

show abstract

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

Solomon,

Ben-Moshe,

Hoffman

et al. 2024

Preprint

View full text Add to dashboard Cite

Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette–Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium ( S .Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.

show abstract

Bacillus Calmette–Guérin–induced interleukin‐10 inhibits S100A8/A9 production and hinders development of T helper type 1 memory in mice

Cited by 4 publications

References 45 publications

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

Helper T cell bias following tuberculosis chemotherapy identifies opportunities for therapeutic vaccination to prevent relapse

Early and Delayed STAT1-Dependent Responses Drive Local Trained Immunity of Macrophages in the Spleen

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