CMPK2 promotes NLRP3 inflammasome activation via mtDNA‐STING pathway in house dust mite‐induced allergic rhinitis

Clinical and Translational Medicine, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 1, 2025

Abstract Background House dust mite (HDM) is the leading allergen for allergic rhinitis (AR). Although sensitisation by inhaled allergens renders susceptible individuals prone to developing AR, molecular mechanisms driving this process remain incompletely elucidated. Objective This study aimed elucidate underlying HDM‐induced AR. Methods We examined expression of cytidine/uridine monophosphate kinase 2 (CMPK2), STING and NLRP3 inflammasome in both AR patients mice. Additionally, we investigated role CMPK2 activation Results The CMPK2, was significantly increased nasal mucosa compared non‐AR controls. A positive correlation found between levels STING, NLRP3, ASC, CASP1 IL‐1β. HDM treatment up‐regulated overexpression enhanced human epithelial cells (HNEPCs). mitochondrial reactive oxygen species (mtROS) production following exposure contributed dysfunction release DNA (mtDNA), which activated cyclic GMP‐AMP synthase (cGAS)‐STING pathway. Remarkably, depletion mtDNA or inhibition signalling reduced HNEPCs. In vivo, genetic knockout alleviated ameliorated clinical symptoms Conclusions Our results suggest that promotes through up‐regulation ensuing mtDNA‐STING pathway, hence revealing additional therapeutic target Key points Cytidine/uridine (CMPK2) mice with caused via (mtDNA)‐STING Blocking house (HDM)‐challenged

Язык: Английский

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Z-DNA at the crossroads: untangling its role in genome dynamics

Trends in Biochemical Sciences, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation

Life Science Alliance, Год журнала: 2025, Номер 8(6), С. e202402921 - e202402921

Опубликована: Апрель 2, 2025

Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause variety of additional pathologies including myopathy. Here, we identified an uncharacterized variant, Q367H, patient diagnosed late-onset distal myopathy, without neuropathy. Supporting hypothesis that this variant contributes to patient’s pathology, fibroblasts and transdifferentiated myoblasts showed changes consistent impairment several functions. We observed mtDNA outside network colocalized early endosomes, measured activation both TLR9 cGAS-STING inflammation pathways sense mtDNA. Re-expressing Q367H KO cells induced release, demonstrating phenotype is direct result variant. As elevated our findings linking signalling explain Thus, characterize novel atypical presentation separates myopathy phenotypes, establish potential pathomechanism connecting dysfunction mtDNA-mediated inflammation.

Язык: Английский

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The cGAS-STING pathway in atherosclerosis

Frontiers in Cardiovascular Medicine, Год журнала: 2025, Номер 12

Опубликована: Апрель 25, 2025

Atherosclerosis (AS), a chronic inflammatory disease, remains leading contributor to cardiovascular morbidity and mortality. Recent studies highlight the critical role of cGAS-STING pathway—a key innate immune signaling cascade—in driving AS progression. This pathway is activated by cytoplasmic DNA from damaged cells, thereby triggering inflammation accelerating plaque formation. While risk factors such as aging, obesity, smoking, hypertension, diabetes are known exacerbate AS, emerging evidence suggests that these may also enhance pathway, which amplifies responses. Targeting this offers promising therapeutic strategy reduce burden diseases (CVD). In review, we summarize mechanisms explore its in evaluate potential inhibitors future candidates. By integrating current knowledge, aim provide insights for developing novel treatments mitigate CVD burden.

Язык: Английский

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Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(49)

Опубликована: Ноя. 27, 2024

Lethal COVID-19 outcomes are attributed to classic cytokine storm. We revisit this using RNA sequencing of nasopharyngeal and 40 autopsy samples from patients dying SARS-CoV-2. Subsets the 100 top-upregulated genes in nasal swabs upregulated heart, lung, kidney, liver, but not mediastinal lymph nodes. Twenty-two these “noncanonical” immune genes, which we link components renin-angiotensin-activation-system that manifest as increased fibrin deposition, leaky vessels, thrombotic tendency, PANoptosis, mitochondrial dysfunction. Immunohistochemistry nodes reveals altered architecture, excess collagen pathogenic fibroblast infiltration. Many above findings paralleled animal models SARS-CoV-2 infection human peripheral blood mononuclear whole individuals with early later variants. then redefine storm lethal driven by upstream gene signaling producing downstream RAAS (renin-angiotensin-aldosterone system) overactivation organ damage, including compromised node function.

Язык: Английский

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Aldehydes, mitophagy, and the pathogenesis of alcohol-associated and metabolic dysfunction-associated steatohepatitis

Elsevier eBooks, Год журнала: 2024, Номер unknown, С. 329 - 361

Опубликована: Ноя. 29, 2024

Язык: Английский

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