| First Author | Xiao S | Year | 2021 |
| Journal | Brain Behav Immun | Volume | 98 |
| Pages | 28-39 | PubMed ID | 34391816 |
| Mgi Jnum | J:312961 | Mgi Id | MGI:6792484 |
| Doi | 10.1016/j.bbi.2021.08.211 | Citation | Xiao S, et al. (2021) Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote atopic dermatitis. Brain Behav Immun 98:28-39 |
| abstractText | The clinical significance and regulators of IL-13Ralpha2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13Ralpha2, 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-13Ralpha2 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-13Ralpha2 transcription levels, and this were downregulated by IL-13Ralpha1KD. IL-13Ralpha2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron-derived IL-13Ralpha2 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 responders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13Ralpha2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13Ralpha2 and TLR2 to modulate neuronal IL-13Ralpha2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13Ralpha2 and neuronal TLR2-IL-13Ralpha2 pathway represent important targets to treat AD and itch. |
