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Pathophysiological Role of TLR4 in Chronic Relapsing Itch Induced by Subcutaneous Capsaicin Injection in Neonatal Rats

  • Hee Joo Kim (Department of Dermatology, Gachon Gil Medical Center, Gachon University College of Medicine) ;
  • Eun-Hui Lee (Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine) ;
  • Yoon Hee Lim (Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine) ;
  • Dongil Jeong (Department of Dermatology, Gachon Gil Medical Center, Gachon University College of Medicine) ;
  • Heung Sik Na (Department of Physiology, Korea University College of Medicine) ;
  • YunJae Jung (Lee Gil Ya Cancer and Diabetes Institute, Gachon University College of Medicine)
  • Received : 2021.09.03
  • Accepted : 2021.12.27
  • Published : 2022.04.30
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Abstract

Despite the high prevalence of chronic dermatitis and the accompanied intractable itch, therapeutics that specifically target itching have low efficacy. Increasing evidence suggests that TLRs contribute to immune activation and neural sensitization; however, their roles in chronic itch remain elusive. Here, we show that the RBL-2H3 mast cell line expresses TLR4 and that treatment with a TLR4 antagonist opposes the LPS dependent increase in mRNA levels of Th2 and innate cytokines. The pathological role of TLR4 activation in itching was studied in neonate rats that developed chronic itch due to neuronal damage after receiving subcutaneous capsaicin injections. Treatment with a TLR4 antagonist protected these rats with chronic itch against scratching behavior and chronic dermatitis. TLR4 antagonist treatment also restored the density of cutaneous nerve fibers and inhibited the histopathological changes that are associated with mast cell activation after capsaicin injection. Additionally, the expression of IL-1β, IL-4, IL-5, IL-10, and IL-13 mRNA in the lesional skin decreased after TLR4 antagonist treatment. Based on these data, we propose that inhibiting TLR4 alleviated itch in a rat model of chronic relapsing itch, and the reduction in the itch was associated with TLR4 signaling in mast cells and nerve fibers.

Keywords

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2021R1A5A2030333 and NRF2021R1C1C1003123).

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