Interleukin-1β (IL-1β) represents one of the most important mediators of inflammation and host responses to infection. Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, induces IL-1β secretion at the site of infection, but the underlying mechanism(s) are poorly understood. In this work we show that Mtb infection of macrophages stimulates caspase-1 activity and promotes the secretion of IL-1β. This stimulation requires live intracellular bacteria expressing a functional ESX-1 secretion system. ESAT-6, an ESX-1 substrate implicated in membrane damage, is both necessary and sufficient for caspase-1 activation and IL-1β secretion. ESAT-6 promotes the access of other immunostimulatory agents such as AG85 into the macrophage cytosol, indicating that this protein may contribute to caspase-1 activation largely by perturbing host cell membranes. Using a high-throughput shRNA-based screen we found that numerous NOD-like receptors (NLRs) and CARD domain-containing proteins (CARDs) were important for IL-1β secretion upon Mtb infection. Most importantly, NLRP3, ASC and caspase-1 form an infection-inducible inflammasome complex that is essential for IL-1β secretion. In summary, we show that recognition of Mtb infection by the NLRP3 inflammasome requires the activity of the bacterial virulence factor ESAT-6, and the subsequent IL-1β response is regulated by a number of NLR/CARD proteins.

The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223^–/– mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223^–/– animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.

Spying on bacterial signals: Many bacteria produce small molecules for monitoring population density and thus regulating their collective behavior, a process termed quorum sensing. Pathogens like Pseudomonas aeruginosa , which complicates cystic fibrosis disease, produce different quorum-sensing ligands at different stages of infection. Moura-Alves et al. used experiments in human cells, zebrafish, and mice to show that a host organism can eavesdrop on these bacterial conversations. A host sensor responds differentially to bacterial quorum-sensing molecules to activate or repress different response pathways. The ability to “listen in” on bacterial signaling provides the host with the capacity to fine-tune physiologically costly immune responses. Science , this issue p. eaaw1629

Background. The recombinant BCG ΔureC::hly (rBCG) vaccine candidate induces improved protection against TB over parental BCG (pBCG) in preclinical studies and has successfully completed a phase IIa clinical trial. However, the mechanisms responsible for superior vaccine efficacy of rBCG are still incompletely understood. Here, we investigated the underlying biological mechanisms elicited by the rBCG vaccine candidate relevant to its protective efficacy.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor of the bHLH/PAS protein family. In this review, we explore the multifaceted roles of AHR in both health and disease, tracing its recognition as a xenobiotic sensor and a central regulator of physiological homeostasis. We begin by recounting six decades of discoveries that have shaped our understanding of AHR, from its canonical function in environmental sensing to its critical roles in development, immune regulation, barrier tissue integrity, and host–microbe interactions. We detail recent structural breakthroughs that have illuminated the ligand-binding mechanisms and regulation of AHR, providing key insights into its activation and transcriptional control. We also highlight the diversity of AHR ligands, ranging from environmental toxins to microbial and dietary metabolites of tryptophan, and their context-dependent effects on AHR activation through the canonical pathway and noncanonical signaling mechanisms. We examine the involvement of AHR in pathologies such as cancer and autoimmune and inflammatory diseases and its potential as a therapeutic target. Finally, emphasis is placed on recent advances and future developments in drug design, aiming to develop modulators with clinical efficacy. This comprehensive synthesis underscores the dual role of AHR as a master integrator of both environmental and endogenous cues. Placing AHR within broader frameworks, such as the exposome, opens new avenues for therapeutic innovation and more effective strategies for disease prevention.