Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

Sebag, Sara C.; Koval, Olha M.; Paschke, J.D.; Winters, Christopher J.; Jaffer, Omar; Dworski, Ryszard; Sutterwala, Fayyaz S.; Anderson, Mark E.; Grumbach, Isabella M.

doi:10.1172/jci.insight.88297

Cited by 51 publications

(54 citation statements)

References 91 publications

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“…However, the source of ROS still remains unknown. Mitochondrial ROS is important for promoting asthma because mitochondrial targeted antioxidant mitoTEMPO showed protection from allergen‐induced asthma . Additionally, NADPH oxidase may also be important .…”

Section: Discussionmentioning

confidence: 99%

Benzo(a)pyrene facilitates dermatophagoides group 1 (Der f 1)‐induced epithelial cytokine release through aryl hydrocarbon receptor in asthma

Wang

Liu

et al. 2019

Allergy

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Background Environmental pollutants, which coexist with allergens, have been associated with the exacerbation of asthma. However, the underlying molecular mechanisms remain elusive. We sought to determine whether benzo(a)pyrene (BaP) co‐exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1‐induced asthma and its underlying mechanisms. Methods The effect of BaP was investigated in Der f 1‐induced mouse model of asthma, including airway hyper‐responsiveness, allergic inflammation, and epithelial‐derived cytokines. The impact of BaP on Der f 1‐induced airway epithelial cell oxidative stress (ROS) and cytokine release was further analyzed. The role of aryl hydrocarbon receptor (AhR) signaling in BaP‐promoted Der f 1‐induced ROS, cytokine production, and allergic inflammation was also investigated. Results Compared with Der f 1, BaP co‐exposure with Der f 1 led to airway hyper‐responsiveness and increased lung inflammation in mouse model of asthma. Increased expression of TSLP, IL‐33, and IL‐25 was also found in the airways of these mice. Moreover, BaP co‐exposure with Der f 1 activated AhR signaling with increased expression of AhR and CYP1A1 and promoted airway epithelial ROS generation and TSLP and IL‐33, but not IL‐25, expression. Interestingly, AhR antagonist CH223191 or cells with AhR knockdown abrogated the increased expression of ROS, TSLP, and IL‐33. Furthermore, ROS inhibitor N‐acetyl‐L‐cysteine (NAC) also suppressed BaP co‐exposure‐induced expression of epithelial TSLP, IL‐33, and IL‐25. Finally, AhR antagonist CH223191 and NAC inhibited BaP co‐exposure with Der f 1‐induced lung inflammation. Conclusions Our findings suggest that BaP facilitates Der f 1‐induced epithelial cytokine release through the AhR‐ROS axis.

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Section: Discussionmentioning

confidence: 99%

Benzo(a)pyrene facilitates dermatophagoides group 1 (Der f 1)‐induced epithelial cytokine release through aryl hydrocarbon receptor in asthma

Wang

Liu

et al. 2019

Allergy

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“…Kim et al found that TiO 2 can lead to NLRP3 inflammasome assembly, which resulted in caspase‐1 activation, mature IL‐1β and IL‐18 excretion, and airway inflammation induction in asthma. Sebag et al found that mitochondrial Ca 2+ /calmodulin‐dependent protein kinase II (CaMKII) mediates ROS production, which stimulates NLRP3 inflammasome activation and promotes inflammation in OVA‐induced asthma, whereas MCC950 (an NLRP3 inhibitor) blocked the Mt‐CaMKII–mediated effects . Using NLRP3‐deficient mice, Besnard AG showed that allergic airway inflammation in OVA‐induced asthma depends on NLRP3 inflammasome activation, which leads to IL‐1β production and Th2 inflammatory response induction .…”

Section: Role Of Nlrp3 Inflammasome In Asthmamentioning

confidence: 99%

NLRP3 inflammasome: A likely target for the treatment of allergic diseases

Xiao

2018

Clin Experimental Allergy

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Allergic diseases, such as asthma, rhinitis, dermatitis, conjunctivitis, and anaphylaxis, have recently become a global public health concern. According to previous studies, the NLRP3 inflammasome is a multi-protein complex known to be associated with many inflammatory conditions. In response to allergens or allergen/damage-associated molecular signals, NLRP3 changes its conformation to allow the assembly of the NLRP3 inflammasome complex and activates caspase-1, which is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines IL-1β and IL-18. Subsequently, active caspase-1 cleaves pro-IL-1 and pro-IL-18. Recently, accumulating human and mouse experimental evidence has demonstrated that the NLRP3 inflammasome, IL-1β, and IL-18 are critically involved in the development of allergic diseases. Furthermore, the application of specific NLRP3 inflammasome inhibitors has been demonstrated in animal models. Therefore, these inhibitors may represent potential therapeutic methods for the management of clinical allergic disorders. This review summarizes findings related to the NLRP3 inflammasome and its related factors and concludes that specific NLRP3 inflammasome inhibitors may be potential therapeutic agents for allergic diseases.

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“…Mice with tamoxifen-inducible Cre recombinase (driven by the SMMHCpromoter) on a C57BL/6 background were obtained from Jackson Laboratories (#019079, denoted as "SM-Cre" mice) 102 . HA-tagged mtCaMKIIN mice were generated by cloning cDNA for the HA-tagged CaMKII inhibitor peptide CaMKIIN (HA-CaMKIIN) fused with the mitochondria targeting Cox8-palmitoylation sequence into a construct containing the CX-1 promoter, a fusion of the chicken beta-actin and CMV promoter, and a floxed eGFP-STOP sequence, and backcrossed with C57BL/6 mice from Jackson Laboratories for at least five generations 103 . Double-transgenic mice with VSMC-specific expression of mtCaMKIIN, denoted as "SM-mtCaMKIIN mice," were generated by crossing SM-Cre mice with HA-tagged mtCaMKIIN mice, as diagrammed in Figure 3…”

Section: Figure 13 Mitochondrial Rho-gtpase Miro-1 Traffics Mitochonmentioning

confidence: 99%

“…Generation of the mitochondrial-targeted CaMKII inhibitor peptide CaMKIIN has been previously described 103 was stopped by adding PMSF at a final concentration of 1 mM, and the mitoplasts were pelleted at 10,000 x g for 10 min and resuspended in MSE with protease inhibitors.…”

Section: Adenoviral Transductionmentioning

confidence: 99%

“…Previous work from our group established CaMKII as a key regulator of VSMC cell migration and proliferation 89,90,110 and of vascular occlusive diseases such as neointimal hyperplasia 90,101 . Emerging studies have suggested that CaMKII resides within the mitochondria of cardiac myocytes 79 and lung epithelial cells 103 , where it modulates mitochondrial matrix Ca 2+ uptake and ROS production. Therefore to investigate whether CaMKII localizes to the mitochondria in VSMC, we performed subcellular fraction of the cytosol and mitochondria.…”

Section: Camkii Is Present and Active In Mitoplastsmentioning

confidence: 99%

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Mitochondrial Ca2+/Calmodulin-dependent kinase ii (CaMKII) regulates smooth muscle cell migration and neointimal formation via mitochondrial Ca2+ uptake and mobility

Nguyen¹

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Mitochondrial CaMKII inhibition in airway epithelium protects against allergic asthma

Cited by 51 publications

References 91 publications

Benzo(a)pyrene facilitates dermatophagoides group 1 (Der f 1)‐induced epithelial cytokine release through aryl hydrocarbon receptor in asthma

Benzo(a)pyrene facilitates dermatophagoides group 1 (Der f 1)‐induced epithelial cytokine release through aryl hydrocarbon receptor in asthma

NLRP3 inflammasome: A likely target for the treatment of allergic diseases

Mitochondrial Ca2+/Calmodulin-dependent kinase ii (CaMKII) regulates smooth muscle cell migration and neointimal formation via mitochondrial Ca2+ uptake and mobility

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