Knockout studies reveal Trim68’s role in reducing IL-33 and inflammatory responses in allergic asthma models, indicating its therapeutic potential.
Description Allergic asthma, a chronic disorder marked by lung inflammation, is associated with significant interleukin-33 (IL-33) production. Alveolar epithelial cells (AECs) are the primary cells damaged by inflammation and initially respond to allergic pathogens. TRIM68, a TRIM family E3 ligase, exhibits high expression in AECs. We found that this highly expression of TRIM68 was significantly inhibited in the lungs of allergic asthma patients. To investigate TRIM68’s role in allergic asthma, we specifically generated TRIM68 totally knockout (Trim68-/-) and AEC conditionally knockout (Trim68f/f, Nkx2-Cre) mice. Upon house dust mite (HDM) extract challenges, TRIM68 depletion markedly enhanced IL-33 production as well as Th2 response related cytokine production in mice. Compared with wild type mice, Trim68-/- mice showed stronger inflammatory infiltration and lung tissue damage upon HDM induction. Notably, Trim68f/f, Nkx2-Cre mice exhibited almost identical responses to Trim68-/- mice, underscoring the critical role of TRIM68 in AECs. Mechanistically, TRIM68 binds to caspase recruitment domain 9 (CARD9) which is the key adaptor in the HDM sensing pathway capable of inducing proinflammatory cytokines. Through this interaction, TRIM68 promotes CARD9 ubiquitination and degradation, consequently reducing IL-33 production. Overall, our findings suggest TRIM68 as a negative regulator in AEC-mediated HDM responses, offering insights into asthma pathogenesis and potential therapies. Funding Sources 1R56AI148215, R01AI155488 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)
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Lu et al. (2025) studied this question.
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