Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis

The clinical significance and regulators of IL-13R alpha 2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13R alpha 2, transcriptomic/pathological analysis was performed in skin from patients with AD, psoriasis, healthy subjects, and murine AD model. Functionality was investigated in sensory neurons, keratinocytes and animal model, by using knockdown (KD), calcium imaging, RNA-seq, cytokine arrays, pharmacological assays, and behavioural investigations. In our study, an upregulated IL-13R alpha 2 expression was revealed in skin of AD patients, but not psoriasis, in a disease activity-dependent manner. In cultured human keratinocytes, IL-13 increased IL-13R alpha 2 transcription levels, and this were downregulated by IL-13R alpha 1KD. IL-13R alpha 2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron- derived IL-13R alpha 2 was upregulated by TLR2 heterodimer agonists, Pam3CSK4 and FSL-1. In a mouse cheek model, pre-administration of Pam3CSK4 and FSL-1 enhanced IL-13-elicited scratching behaviour. Consistently, in cultured sensory neurons Pam3CSK4 enhanced IL-13-elicted calcium transients, increased number of re- sponders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13R alpha 2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13R alpha 2 and TLR2 to modulate neuronal IL-13R alpha 2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13R alpha 2 and neuronal TLR2-IL-13R alpha 2 pathway represent important targets to treat AD and itch.