bims-inflin 2025-03-23 papers

PLoS Pathog. 2025 Mar;21(3): e1012108

NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminth Schistosoma mansoni.

Madhusoodhanan Suresh Kumar Meena Kumari, Pengyu Liu, Megan S Nitchman, Santoshi Chaudhary, Kaile Jump, Yoelkys Morales, Emily A Miller, Ilana Shecter, Miguel J Stadecker, Parisa Kalantari.

Infection with the helminth Schistosoma mansoni can cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1β secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1β suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome- mediated IL-1β production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.

DOI: https://doi.org/10.1371/journal.ppat.1012108

bioRxiv. 2025 Mar 07. pii: 2024.12.11.627830. [Epub ahead of print]

NLRP11 is required for canonical NLRP3 and non-canonical inflammasome activation during human macrophage infection with mycobacteria.

Mateusz Szczerba, Akshaya Ganesh, Maria Luisa Gil-Marques, Volker Briken, Marcia B Goldberg.

The NLRP11 protein is only expressed in primates and participates in the activation of the canonical NLRP3 and non-canonical NLRP3 inflammasome activation after infection with gram-negative bacteria. Here, we generated a series of defined NLRP11 deletion mutants to further analyze the role of NLRP11 in NLRP3 inflammasome activation. Like the complete NLRP11 deletion mutant ( NLRP11 -/- ), the NLRP11 mutant lacking the NACHT and LRR domains ( NLRP11 ∆ N_LRR ) showed reduced activation of the canonical NLRP3 inflammasome, whereas a pyrin domain mutant ( NLRP11 ∆ PYD ) had no effect on NLRP3 activation. The NLRP11 -/- and NLRP11 ∆ N_LRR mutants but not the NLRP11 ∆ PYD mutant also displayed reduced activation of caspase-4 during infection with the intracytosolic, gram-negative pathogen Shigella flexneri . We found that the human adapted, acid-fast pathogen Mycobacterium tuberculosis and the opportunistic pathogen M. kansasii both activate the non-canonical NLRP11 inflammasome in a caspase-4/5-dependent pathway. In conclusion, we show that NLRP11 functions in the non-canonical caspase-4/5 inflammasome activation pathway and the canonical NRLP3 inflammasome pathway, and that NLRP11 is required for full recognition of mycobacteria by each of these pathways. Our work extends the spectrum of bacterial pathogen recognition by the non-canonical NLRP11-caspase4/5 pathway beyond gram-negative bacteria.

DOI: https://doi.org/10.1101/2024.12.11.627830

Cell Death Dis. 2025 Mar 17. 16(1): 181

Ubiquitination of gasdermin D N-terminal domain directs its membrane translocation and pore formation during pyroptosis.

Xiufeng Chu, Ting Zhang, Ihtisham Bukhari, Mei Hu, Jixuan Xu, Yamin Xing, Xinfeng Liang, Zisen Zhang, Pengyuan Zheng.

Gasdermin D (GSDMD) is a critical pyroptosis mediator, consisting of one N-terminal pore-forming domain and one C-terminal auto-inhibitory domain. The free N-terminal domain (GD-NT), which is released through caspase-1/11 cleavage, exhibits distinct features from the full-length GSDMD (GD-FL), including oligomerization, membrane translocation, and pore-formation. However, the underlying mechanisms are not well elucidated. Here, we found that GD-NT, but not GD-FL, was massively ubiquitinated in cells. The K63-linked polyubiquitination of GD-NT at Lys236/237 (human/mouse), catalyzed by TRAF1, directly prompted its membrane translocation and pore-formation during pyroptosis. Inhibition of GD-NT ubiquitination via site-directed mutations or the UBA1 inhibitor PYR-41 suppressed cell death in several pyroptosis cell models. Additionally, applying PYR-41 in septic mice efficiently suppressed the release of IL-18 and TNFα. Thus, GD-NT ubiquitination is a key regulatory mechanism controlling its membrane localization and activation, which may provide a novel target for modulating immune activity in pyroptosis-related diseases.

DOI: https://doi.org/10.1038/s41419-025-07475-6

Front Immunol. 2025 ;16 1553093

Suppression of NLRP3 inflammasome by a small molecule targeting CK1α-β-catenin-NF-κB and CK1α-NRF2-mitochondrial OXPHOS pathways during mycobacterial infection.

Qing Guan, Huan Xiong, Xiangyu Song, Sheng Liu, Yuanjun Guang, Qi Nie, Yan Xie, Xiao-Lian Zhang.

Introduction: Pyroptosis is an important inflammatory form of cell death and Mycobacterium tuberculosis (M.tb) chronic infection triggers excessive inflammatory pyroptosis of macrophages. Our previous research has confirmed that a small compound pyrvinium pamoate (PP) could inhibit inflammatory pathological changes and mycobacterial burden in M.tb-infected mice, but the potential mechanism of PP for inhibiting M.tb-induced inflammation remains unexplored.
Methods: The effects of PP on the NLRP3-ASC-Casp1 inflammasome assembly and activation, gasdermin D (GSDMD) mediated pyroptosis and inflammatory cytokines expression were assessed in human THP-1-derived macrophages after M.tb H37Rv/H37Ra/ Salmonella typhimurium (S. typhimurium) infection or LPS treatment by Transcriptome sequencing, RT-qPCR, Co-immunoprecipitation and Western Blot (WB) analysis. The lactate dehydrogenase (LDH) release assay was used to evaluate the CC50 of PP in M.tb-infected THP-1 cells.
Results: We found that M.tb/S. typhimurium infection and LPS treatment significantly activate NLRP3-ASC-Casp1 inflammasome activation, GSDMD-mediated pyroptosis and inflammatory cytokines (IL-1β and IL-18) expression in macrophages, whereas PP could suppress these inflammatory effects in a dose dependent manner. Regarding the PP-inhibition mechanism, we further found that this inhibitory activity is mediated through the PP-targeting casein kinase 1A1 (CK1α)-β-catenin-NF-κB pathway and CK1α-NRF2-mitochondrial oxidative phosphorylation (OXPHOS) pathway. In addition, a CK1α specific inhibitor D4476 or CK1α siRNA could reverse these inhibitory effects of PP on bacteria-induced inflammatory responses in macrophages.
Conclusions: This study reveals a previously unreported mechanism that pyrvinium can inhibit NLRP3 inflammasome and GSDMD-IL-1β inflammatory pyroptosis via targeting suppressing CK1α-β-catenin-NF-κB and CK1α-NRF2-mitochondrial OXPHOS pathways, suggesting that pyrvinium pamoate holds great promise as a host directed therapy (HDT) drug for mycobacterial-induced excessive inflammatory response.

Keywords: CK1α-NRF2-mitochondrial OXPHOS pathway; CK1α-β-catenin-NF-κB pathway; GSDMD; NLRP3 inflammasome; mycobacterium tuberculosis; pyroptosis; pyrvinium pamoate

DOI: https://doi.org/10.3389/fimmu.2025.1553093

Nat Commun. 2025 Mar 17. 16(1): 2626

IL-1 protects from fatal systemic candidiasis in mice by inhibiting oxidative phosphorylation and hypoxia.

Sofia Horn, Mareike Schmid, Ivan Berest, Federica Piattini, Jing Zhang, Katrien de Bock, Olivier Devuyst, Stellor Nlandu Khodo, Jan Kisielow, Manfred Kopf.

Invasive C. albicans infections result in high mortality rates. While IL-1 is important to combat C. albicans infections, the underlying mechanisms remain unclear. Using global and conditional Il1r1 knockouts in mice, here we show that IL-1R signaling in non-hematopoietic cells in the kidney and brain is crucial for a protective response. In the kidney, endothelial IL-1R contributes to fungal clearance independent of neutrophil recruitment, while IL-1R in hematopoietic cells is dispensable. IL-1R signaling indirectly recruits neutrophils and monocytes in the brain by regulating chemokines and adhesion molecules. Single-nucleus-RNA-sequencing data implicates excessive metabolic activity and oxidative phosphorylation across all cell types in the kidney of Il1r1-deficient mice within a few hours upon infection, with associated, localized hypoxia at infection foci. Lastly, we find that hypoxia promotes fungal growth and pathogenicity. In summary, our results show that IL-1R-signaling in non-hematopoietic cells is required to prevent fatal candidiasis by inhibiting a metabolic shift, including excessive oxidative phosphorylation and hypoxia.

DOI: https://doi.org/10.1038/s41467-025-57797-4

Elife. 2025 Mar 17. pii: RP91329. [Epub ahead of print]12

Inhibiting NINJ1-dependent plasma membrane rupture protects against inflammasome-induced blood coagulation and inflammation.

Jian Cui, Hua Li, Dien Ye, Guoying Zhang, Yan Zhang, Ling Yang, Martha M S Sim, Jeremy P Wood, Yinan Wei, Zhenyu Li, Congqing Wu.

Systemic blood coagulation accompanies inflammation during severe infections like sepsis and COVID. We previously established a link between coagulopathy and pyroptosis, a vital defense mechanism against infection. During pyroptosis, the formation of gasdermin-D (GSDMD) pores on the plasma membrane leads to the release of tissue factor (TF)-positive microvesicles (MVs) that are procoagulant. Mice lacking GSDMD release fewer of these procoagulant MVs. However, the specific mechanisms coupling the activation of GSDMD to MV release remain unclear. Plasma membrane rupture (PMR) in pyroptosis was recently reported to be actively mediated by the transmembrane protein Ninjurin-1 (NINJ1). Here, we show that NINJ1 promotes procoagulant MV release during pyroptosis. Haploinsufficiency or glycine inhibition of NINJ1 limited the release of procoagulant MVs and inflammatory cytokines, and partially protected against blood coagulation and lethality triggered by bacterial flagellin. Our findings suggest a crucial role for NINJ1-dependent PMR in inflammasome-induced blood coagulation and inflammation.

Keywords: Coagulation; Infection; Inflammasome; Macrophage; Microvesicle; NINJ1; Pyroptosis; Sepsis; immunology; inflammation; mouse

DOI: https://doi.org/10.7554/eLife.91329