ETS2 aggravate allergic airway inflammation by regulating ANT2-mediated cytosolic mitochondrial DsRNA levels

ETS2 aggravate allergic airway inflammation by regulating ANT2-mediated cytosolic mitochondrial DsRNA levels

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Abstract Background ETS2 has been identified as a pivotal regulator in the development of human inflammatory diseases.Nevertheless, the functional aspects of ETS2 in asthma remain inadequately characterized.The release of mitochondrial Hockey Accessories - Tape dsRNA is recognized as an initiator of innate immune responses and implicated in intensifying inflammation triggered by alternative immunogens.The interplay between these mechanisms remains poorly understood, and only a limited number of direct targets that underpin the pro-inflammatory role of ETS2 have been identified.Methods The expression of ETS2 in epithelial cells under immune responses was analyzed, and its effects on asthma progression were examined through clinical specimens, human bronchial epithelial cells, and an allergic asthma mouse model.

Additionally, the potential involvement of adenine nucleotide translocase-2 in mediating the immune responses regulated by ETS2 was explored.Results Increased expression of ETS2 in lung epithelial cells was observed in both asthma patients and ovalbumin (OVA)-induced asthma mice.The deficiency of ETS2 resulted in a substantial decline in inflammatory cell infiltration and markedly diminished IL-6, IL-5, and IL-13 levels in epithelial cells.Mechanistically, ETS2 overexpression was associated with elevated cytosolic mitochondrial RNA levels, whereas knockdown resulted in their suppression.Furthermore, adenine nucleotide translocase-2 (ANT2) expression was robustly upregulated by ETS2 through direct promoter binding.

The advantageous effects of ETS2 on asthma development were abrogated in ANT2-deficient mice.Conclusions The findings collectively underscore the role of ETS2 Upper Frame Cap as an exacerbating factor in allergic airway inflammation during asthma progression, primarily by inducing ANT2 expression.Therapeutic targeting of epithelial ETS2 could represent a novel approach to asthma management.Clinical trial number Not applicable.