bims-inflin 2025-04-20 papers

J Immunol. 2025 Apr 18. pii: vkaf042. [Epub ahead of print]

Innate immune sensor NLRP3 drives PANoptosome formation and PANoptosis.

Bhesh Raj Sharma, Sk Mohiuddin Choudhury, Hadia M Abdelaal, Yaqiu Wang, Thirumala-Devi Kanneganti.

Inflammasomes are multiprotein innate immune complexes formed in response to infections, tissue damage, or cellular stress that promote the maturation and release of IL-1β/IL-18 and are implicated in lytic cell death. The NLRP3 inflammasome is canonically activated by an initial priming event followed by an activation stimulus, leading to rapid cell death that occurs through caspase-1 (CASP1) and gasdermin D (GSDMD) activation, called pyroptosis. CASP1- and GSDMD-deficient cells are protected from the rapid LPS plus ATP-induced pyroptosis. However, innate immune responses physiologically occur over time, extending beyond minutes to hours and days. Therefore, in this study, we assessed lytic cell death beyond the early timepoints. While cells lacking the innate immune sensor NLRP3 were protected from cell death induced by the canonical NLRP3 trigger, LPS priming and ATP stimulation (LPS plus ATP), for extended time, CASP1- and GSDMD-deficient cells started to lyse in a time-dependent manner after 2 h. Nevertheless, robust IL-1β and IL-18 release was still dependent on CASP1 activation. These data suggested that NLRP3 engages an additional innate immune, lytic cell death pathway. Indeed, LPS plus ATP induced the activation of caspases and RIPKs associated with PANoptosis in WT cells, and cells deficient in PANoptosis machinery were protected from cell death for extended times. A PANoptosome complex containing NLRP3, ASC, CASP8, and RIPK3 was observed by microscopy in WT, as well as CASP1- or GSDMD-deficient, cells by 30 min post-stimulation. Overall, these findings highlight the central role of NLRP3 as a PANoptosome sensor. Given the physiological role of innate immune cell death, PANoptosis, in health and disease, our study emphasizes the importance of a comprehensive understanding of PANoptosomes, and their components, as therapeutic targets.

Keywords: PANoptosome; RIPK; caspase; inflammasome; inflammation

DOI: https://doi.org/10.1093/jimmun/vkaf042

Int J Biol Macromol. 2025 Apr 12. pii: S0141-8130(25)03574-3. [Epub ahead of print]309(Pt 4): 143022

Serine protease Rv2569c inhibits inflammatory response and promotes intracellular survival of Mycobacterium tuberculosis by targeting the RhoG-NF-κB-NLRP3 pathway.

Xinxin Zang, Jiajun Zhang, Tingting Feng, Hui Wang, Yingying Cui, Yanyan Jiang, Chunwen Chen, Siguo Liu, Guanghui Dang.

Innate immunity is dominant in protecting the host's defense against intracellular bacterial infections. The secretion of IL-1β and activation of NLRP3 inflammasome in macrophages play a critical role in combating Mycobacterium tuberculosis (M.tb) infections. M.tb is an extremely successful intracellular pathogen that evades host innate immunity by interfering with a wide range of macrophage functions. However, the precise infection mechanism remains unclear. This study demonstrates that the mycobacterial serine protease Rv2569c interacts with RhoG in macrophages, effectively blocking the NF-κB signaling pathway's initiation and suppressing NLRP3 inflammasome activation, ultimately leading to a decrease in IL-1β secretion and promoting mycobacterial survival within macrophages. To investigate the role of Rv2569c in M.tb infection, an Rv2569c-deficient strain (H37RvΔRv2569c) was used to demonstrate a weakened suppression of the inflammatory response and lower intracellular survival compared to the wild-type (H37Rv) and complemented strain (H37RvΔRv2569c + Rv2569c) through in vitro and in vivo experiments. The findings provide the first proof that RhoG serves as an endogenous host sensor for pathogens and that Rv2569c-RhoG-mediated inflammatory response plays a crucial role in mycobacterial immune evasion.

Keywords: Mycobacterium tuberculosis Rv2569c; NF-κB signaling pathway; NLRP3 inflammasome

DOI: https://doi.org/10.1016/j.ijbiomac.2025.143022

Nat Microbiol. 2025 Apr 18.

Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence.

Wenjun Xia, Youxiang Mao, Ziyan Xia, Jie Cheng, Peng Jiang.

Metabolic remodelling underpins macrophage effector functions in response to various stimuli, but the mechanisms involved are unclear. Here we report that viral-infection-induced inflammatory stimulation causes a rewiring of the urea cycle and the tricarboxylic acid cycle metabolism in macrophages to form a cyclic pathway called the aspartate-argininosuccinate (AAS) shunt. Using RNA sequencing, unbiased metabolomics and stable isotope tracing, we found that fumarate generated from the AAS shunt is driven by argininosuccinate synthase (ASS1) in the cytosol and potentiates inflammatory effects. Genetic ablation of ASS1 reduces intracellular fumarate levels and interferon-β production, and mitochondrial respiration is also suppressed. Notably, viral challenge or fumarate esters enhance interferon-β production via direct succination of the mitochondrial antiviral signalling protein and activation of the retinoic acid-inducible gene-I-like receptor signalling. In addition to the vesicular stomatitis virus, the Sendai virus and influenza A virus can also exert these effects. In addition, patients with Ebola virus disease have increased ASS1 expression and ASS1-deficient mice show suppressed macrophage interferon responses to vesicular stomatitis virus infection. These findings reveal that fumarate can be produced from the viral inflammation-induced AAS shunt and is essential for antiviral innate immunity.

DOI: https://doi.org/10.1038/s41564-025-01985-x

mBio. 2025 Apr 16. e0018925

Mechanisms and immune crosstalk of neutrophil extracellular traps in response to infection.

Qi Liu, Ruke Chen, Ziyan Zhang, Zhou Sha, Haibo Wu.

Neutrophil extrusion of neutrophil extracellular traps (NETs) in a process called NETosis provides immune defense against extracellular bacteria. It has been observed that bacteria are capable of activating neutrophils to release NETs that subsequently kill them or at least prevent their local spread within host tissue. However, existing studies have mainly focused on the isolated function of NETs, with less attention given to their anti-bacterial mechanisms through interactions with other immune cell populations. The net effect of these complex intercellular interactions, which may act additively, synergistically, or antagonistically, is a critical determinant in the outcomes of host-pathogen interactions. This review summarizes the mechanisms underlying classic NET formation and their crosstalk with the immune system, offering novel insights aimed at balancing the anti-microbial function with their potential inflammatory risks.

Keywords: adaptive immunity; bacterial infection; evasion; innate immunity; neutrophil; neutrophil extracellular traps (NETs)

DOI: https://doi.org/10.1128/mbio.00189-25