bims-inflin 2025-05-04 papers

PLoS One. 2025 ;20(5): e0322127

IL-18 production is required for the generation of a Th1 response during experimental chromoblastomycosis.

Lucas Golçalves Ferreira, Sandro Rogério de Almeida.

Chromoblastomycosis is a chronic fungal infection characterized by the formation of granulomatous lesions in the skin and subcutaneous tissues that begins after inoculation trauma. The disease is more frequently observed in tropical countries such as Brazil. Important studies have been shown a predominantly cell-mediated immune response during chromoblastomycosis. Results from our laboratory showed that Th1 responses are essential to induce protection during chromoblastomycosis. IL-18 is primarily produced by macrophages and is known to induce the production of IFNγ, a cytokine associated with Th1 cell activation. Once produced, IL-18 acts to promote Th1 cell differentiation and activation. Th1 cells, in turn, secrete cytokines such as IFNγ, which are critical for the elimination of intracellular pathogens, including fungi. IFNγ enhances the fungicidal activity of macrophages, promotes the development of antifungal effector mechanisms, and contributes to the containment of fungal growth. Our results indicate that F. pedrosoi is sensed by the NLRP3 inflammasome, which induces caspase-1 activation and production of IL-18. Moreover, IL-18 plays a crucial role in activating Th1 cells and controlling fungal loads during chromoblastomycosis. Further research into the mechanisms underlying IL-18-mediated immunity may lead to the development of novel therapeutic approaches for the treatment of this chronic fungal infection.

DOI: https://doi.org/10.1371/journal.pone.0322127

Cell Rep. 2025 Apr 27. pii: S2211-1247(25)00395-X. [Epub ahead of print]44(5): 115624

Staphylococcus aureus promotes strain-dependent immunopathology during cutaneous leishmaniasis through induction of IL-1β.

Victoria Lovins, Camila Farias Amorim, Nélida Robles, Sofía Murga-Garrido, Jamie Ting-Chun Pan, Tej P Singh, Erin DeNardo, Lucas P Carvalho, Edgar M Carvalho, Phillip Scott, Elizabeth A Grice.

Cutaneous leishmaniasis is a parasitic infection that causes a spectrum of pathology ranging from single, self-healing lesions to disfiguring chronic wounds. In severe disease, uncontrolled inflammation exacerbates tissue damage and delays healing, though the contributing factors are unclear. We previously observed that delayed healing was associated with Staphylococcus aureus in the lesional microbiota of patients with cutaneous leishmaniasis. To investigate how S. aureus impacts immunopathology during leishmania infection, we established a murine model of S. aureus colonization with clinical isolates followed by Leishmania infection. S. aureus triggered early production of interleukin (IL)-1β during Leishmania infection, which was critical for neutrophil recruitment and cutaneous inflammation. S. aureus isolates differentially induced IL-1β and neutrophil recruitment, and isolates that induced greater neutrophil recruitment were resistant to neutrophil killing and persisted longer. We reveal a mechanism whereby S. aureus mediates immunopathology during cutaneous leishmaniasis, suggesting IL-1β as a promising immunomodulatory target for non-healing infections.

Keywords: CP: Microbiology; Leishmania; Staphylococcus aureus; cutaneous leishmaniasis; microbiota; skin infection

DOI: https://doi.org/10.1016/j.celrep.2025.115624

Nature. 2025 Apr 30.

Diet outperforms microbial transplant to drive microbiome recovery in mice.

M S Kennedy, A Freiburger, M Cooper, K Beilsmith, M L St George, M Kalski, C Cham, A Guzzetta, S C Ng, F K Chan, O DeLeon, D Rubin, C S Henry, J Bergelson, E B Chang.

A high-fat, low-fibre Western-style diet (WD) induces microbiome dysbiosis characterized by reduced taxonomic diversity and metabolic breadth1,2, which in turn increases risk for a wide array of metabolic3-5, immune6 and systemic pathologies. Recent work has established that WD can impair microbiome resilience to acute perturbations such as antibiotic treatment7,8, although little is known about the mechanism of impairment and the specific consequences for the host of prolonged post-antibiotic dysbiosis. Here we characterize the trajectory by which the gut microbiome recovers its taxonomic and functional profile after antibiotic treatment in mice on regular chow (RC) or WD, and find that only mice on RC undergo a rapid successional process of recovery. Metabolic modelling indicates that a RC diet promotes the development of syntrophic cross-feeding interactions, whereas in mice on WD, a dominant taxon monopolizes readily available resources without releasing syntrophic byproducts. Intervention experiments reveal that an appropriate dietary resource environment is both necessary and sufficient for rapid and robust microbiome recovery, whereas microbial transplant is neither. Furthermore, prolonged post-antibiotic dysbiosis in mice on WD renders them susceptible to infection by the intestinal pathogen Salmonella enterica serovar Typhimurium. Our data challenge widespread enthusiasm for faecal microbiota transplant (FMT) as a strategy to address dysbiosis, and demonstrate that specific dietary interventions are, at a minimum, an essential prerequisite for effective FMT, and may afford a safer, more natural and less invasive alternative.

DOI: https://doi.org/10.1038/s41586-025-08937-9

Mol Med Rep. 2025 Jul;pii: 185. [Epub ahead of print]32(1):

NLRP3 inflammasome expression affects immune cell infiltration and clinical prognosis in Helicobacter pylori infection‑associated gastric cancer.

Chuandan Wan, Yeqiong Xu, Yanping Zhu, Xuexian Cao, Ping Wang, Yulan Gu.

High Helicobacter pylori infection rates contribute to high gastric cancer (GC) incidence. While H. pylori infection is associated with GC development its mechanisms are still being studied. The aim of the present study was to examine the differences between H. pylori infection‑induced GC and non‑infected tissues, and to investigate the correlation between nucleotide‑binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome expression and immune cell infiltration in GC, thus providing a theoretical basis for clinical prognosis and immunotherapy. High‑throughput RNA‑sequencing expression data from The Cancer Genome Atlas (TCGA) were analyzed. Additionally, TIMER2.0 and Kaplan‑Meier Plotter were used to analyze the differential expression of NLRP3 mRNA in various tumors, the effect of H. pylori infection on gene expression, and the association between NLRP3 and clinical prognosis among patients with GC. Immunohistochemistry (IHC) was used to assess the effects of NLRP3 protein expression on immune cell infiltration in clinical tissues with or without H. pylori infection. R software was used for data visualization and statistical analysis. TCGA data revealed that the expression levels of NLRP3 in GC tissues were increased compared with those in normal tissues (P<0.05), which was further validated in clinical samples. Furthermore, NLRP3 mRNA expression was significantly elevated in clinical GC tissues infected with H. pylori. Notably higher relative levels of NLRP3 mRNA were observed in tumor tissues with a tumor size ≥5 cm, lymph node metastasis, Tumor‑Node‑Metastasis stage III + IV or poor differentiation compared with the respective controls (P<0.05). IHC confirmed a significant increase in NLRP3 expression within H. pylori‑infected GC tissues compared with that in non‑infected tissues. In GC immune infiltration, NLRP3 expression was revealed to be associated with natural killer cell, whereas it was negatively correlated with regulatory T cells and CD8+ T cells. These findings indicated that NLRP3 may promote the polarization of tumor‑associated macrophages towards the M2 phenotype. High NLRP3 expression also promoted the infiltration of CD3+ and CD206+ cells, which significantly affected the survival rate of patients with GC. The immune infiltration of regulatory T lymphocytes was associated with better survival benefits for patients with GC; however, M2 macrophage infiltration was not conducive to the survival of patients with GC. Furthermore, survival analysis showed that high expression of NLRP3 was associated with a poorer 5‑year overall survival, progression‑free survival and post‑progression survival rates. In conclusion, elevated NLRP3 expression, which may be induced by H. pylori infection, could promote immune cell infiltration potentially by regulating cancer cell proliferation and migration, ultimately leading to an unfavorable prognosis and a notable reduction in the 5‑year survival rate.

Keywords: Helicobacter pylori; NLRP3 inflammasome; gastric cancer; immune cell infiltration; immunotherapy; prognosis

DOI: https://doi.org/10.3892/mmr.2025.13550

FEBS J. 2025 Apr 28.

Glutamine limits NLRP3 inflammasome activation and pyroptosis in macrophages by sustaining the IRG1/itaconate axis.

Xiaoli Chen, Yuanfeng Zhu, Lin Xia, Sen Su, Shijun Fan, Yongling Lu, Qian Chen, Yan Wei, Qianying Huang, Xin Liu, Xi Peng.

Aberrant activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome increases the release of mature pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and enhances pyroptosis; thereby necessitating tight regulation of the NLRP3 inflammasome. Dysfunctional glutamine metabolism contributes to the pathogenesis of multiple inflammatory disorders, and the precise mechanism remains to be elucidated. Here, we provide evidence that glutamine deprivation enhances NLRP3 inflammasome activation in macrophages. Indeed, the absence of exogenous glutamine specifically enhanced NLRP3 inflammasome assembly, thereby accelerating pyroptosis and promoting the maturation of IL-1β and IL-18. Inhibition of glutaminolysis exhibited a similar effect to glutamine deprivation, whereas this effect was reversed by α-ketoglutarate (α-KG), a tricarboxylic acid (TCA)-cycle intermediate that can be replenished by glutamine supply. We further observed reduced generation of endogenous itaconate by glutamine deprivation and verified that both exogenous supplementation of itaconate derivative and increased endogenous itaconate production by overexpressing immune-responsive gene 1 [IRG1; also known as aconitate decarboxylase 1 (ACOD1)] could replace glutamine to inhibit the NLRP3 inflammasome. Mechanistically, glutamine deprivation decreased the source of substrate and inhibited transcription factor EB (TFEB)-dependent transcriptional upregulation of IRG1, thereby impairing the IRG1/itaconate axis that suppresses the NLRP3 inflammasome. Furthermore, glutamine deficiency was detected in a murine sepsis model, whereas extrinsic glutamine supplementation conferred protection against intestinal inflammation and tissue damage in septic mice. Taken together, our findings provide a novel insight into the link between glutamine metabolism and NLRP3 inflammasome activation, highlighting the target of glutamine metabolism, which holds as a potential therapeutic strategy for inflammatory diseases.

Keywords: IRG1/itaconate axis; NLRP3 inflammasome; glutamine metabolism; itaconate; pyroptosis

DOI: https://doi.org/10.1111/febs.70119