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CMPK2 promotes NLRP3 inflammasome activation via mtDNA-STING pathway in house dust mite-induced allergic rhinitis
YaoMing Zheng1, YaDong Xie1,2, JiaYing Li1
1Allergy Center, Department of Otolaryngology, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, China.
Background:
House dust mite (HDM) is the leading allergen for allergic rhinitis (AR). Although allergic sensitisation by inhaled allergens renders susceptible individuals prone to developing AR, the molecular mechanisms driving this process remain incompletely elucidated.
Objective:
This study aimed to elucidate the molecular mechanisms underlying HDM-induced AR.
Methods:
We examined the expression of cytidine/uridine monophosphate kinase 2 (CMPK2), STING and the NLRP3 inflammasome in both AR patients and mice. Additionally, we investigated the role of CMPK2 and STING in the activation of the NLRP3 inflammasome in AR.
Results:
The expression of CMPK2, STING and the NLRP3 inflammasome was significantly increased in the nasal mucosa of AR patients compared to non-AR controls. A positive correlation was found between CMPK2 expression and the levels of STING, NLRP3, ASC, CASP1 and IL-1β. HDM treatment up-regulated the expression of CMPK2, and CMPK2 overexpression enhanced NLRP3 inflammasome activation in human nasal epithelial cells (HNEPCs). Additionally, mitochondrial reactive oxygen species (mtROS) production following HDM exposure contributed to mitochondrial dysfunction and the release of mitochondrial DNA (mtDNA), which activated the cyclic GMP-AMP synthase (cGAS)-STING pathway. Remarkably, depletion of mtDNA or inhibition of STING signalling reduced HDM-induced NLRP3 inflammasome activation in HNEPCs. In vivo, genetic knockout of CMPK2 or STING alleviated NLRP3 inflammasome activation and ameliorated clinical symptoms of AR in mice.
Conclusions:
Our results suggest that HDM promotes the activation of NLRP3 inflammasome through the up-regulation of CMPK2 and ensuing mtDNA-STING signalling pathway, hence revealing additional therapeutic target for AR.
Key Points:
Cytidine/uridine monophosphate kinase 2 (CMPK2) expression is up-regulated in the nasal mucosa of patients and mice with allergic rhinitis (AR). CMPK2 caused NLRP3 inflammasome activation via mitochondrial DNA (mtDNA)-STING pathway. Blocking CMPK2 or STING signalling significantly reduced the activation of NLRP3 in house dust mite (HDM)-challenged mice and human nasal epithelial cells (HNEPCs).
Insights
House dust mite allergy triggers allergic rhinitis (AR) by up-regulating CMPK2, which activates the NLRP3 inflammasome via the mtDNA-STING pathway. Targeting CMPK2 or STING offers a new therapeutic strategy for AR.
Area of Science:
- Immunology
- Molecular Biology
- Allergy Research
Background:
- House dust mite (HDM) is a primary allergen responsible for allergic rhinitis (AR).
- The precise molecular mechanisms linking inhaled allergens to AR development are not fully understood.
Purpose of the Study:
- To investigate the molecular pathways involved in HDM-induced allergic rhinitis.
- To elucidate the role of CMPK2 and STING in NLRP3 inflammasome activation.
Main Methods:
- Examined CMPK2, STING, and NLRP3 inflammasome expression in AR patients and mice.
- Investigated CMPK2 and STING's role in NLRP3 inflammasome activation in human nasal epithelial cells (HNEPCs) and mouse models.
- Assessed mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) release.
Main Results:
- CMPK2, STING, and NLRP3 inflammasome components were elevated in AR nasal mucosa.
- HDM exposure upregulated CMPK2, enhancing NLRP3 inflammasome activation via the mtDNA-STING pathway.
- Inhibition of CMPK2 or STING, or depletion of mtDNA, reduced NLRP3 activation and AR symptoms in vivo and in vitro.
Conclusions:
- HDM induces NLRP3 inflammasome activation through CMPK2-mediated mtDNA-STING signaling.
- CMPK2 and the mtDNA-STING pathway represent potential therapeutic targets for AR treatment.
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