Misregulation of T-box transcription factors drives BNP-NPR1 signalling underlying chronic itch.
basic_science · Level V
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- Record sourced from PubMed, PMID 42469239.
- Also identified by DOI 10.1038/s41467-026-75726-x.
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Abstract
Chronic itch poses a significant clinical burden, with activation of the brain natriuretic peptide (BNP) pathway as a hallmark, though its transcriptional control remains unclear. We identify T-box transcription factor 20 (TBX20) as upregulated in skin of atopic dermatitis patients, with increased expression in NPR1<sup>+</sup> keratinocytes. ChIP peak calling, ChIP-qPCR and dual-luciferase assays show TBX20 activates the NPR1 promoter. In mice, keratinocyte-specific TBX20 knockout (TBX20<sup>fl/fl</sup>; K14-Cre) reduces scratching, IL-4 and Oncostatin M levels, basophil markers, and decreases cutaneous NPR1 expression. TBX20 is also expressed in a subset of NPR1<sup>+</sup> sensory neurons, and neuron-specific deletion similarly alleviates itch, basophil infiltration, and barrier dysfunction. RNA-seq identifies lipocalin-2 as a downstream effector of the TBX20-NPR1 axis, and its deletion reduces itch. Conversely, AAV-mediated TBX20 rescue exacerbates symptoms. Neuregulin 1 suppresses TBX20, attenuates IL-13-driven NPR1 signalling, and reduces itch. These findings define a TBX20-NPR1 axis as a critical regulator of chronic itch and skin dysfunction.