PMID- 34391816
OWN - NLM
STAT- MEDLINE
DCOM- 20211210
LR  - 20220531
IS  - 1090-2139 (Electronic)
IS  - 0889-1591 (Linking)
VI  - 98
DP  - 2021 Nov
TI  - Innate immune regulates cutaneous sensory IL-13 receptor alpha 2 to promote 
      atopic dermatitis.
PG  - 28-39
LID - S0889-1591(21)00501-8 [pii]
LID - 10.1016/j.bbi.2021.08.211 [doi]
AB  - 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.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Xiao, Song
AU  - Xiao S
AD  - School of Life Sciences, Henan University, China.
FAU - Lu, Zhiping
AU  - Lu Z
AD  - School of Life Sciences, Henan University, China.
FAU - Steinhoff, Martin
AU  - Steinhoff M
AD  - Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, 
      Qatar; Translational Research Institute, Academic Health System, Hamad Medical 
      Corporation, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad 
      Medical Corporation, Doha, Qatar; Department of Dermatology, Weill Cornell 
      Medicine-Qatar, Doha, Qatar; Qatar University, College of Medicine, Doha, Qatar; 
      Department of Dermatology, Weill Cornell Medicine, New York, USA.
FAU - Li, Yanqing
AU  - Li Y
AD  - School of Life Sciences, Henan University, China.
FAU - Buhl, Timo
AU  - Buhl T
AD  - Department of Dermatology, Venereology and Allergology, University Medical Centre 
      Gottingen, Germany.
FAU - Fischer, Michael
AU  - Fischer M
AD  - Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, 
      Austria.
FAU - Chen, Weiwei
AU  - Chen W
AD  - School of Life Sciences, Henan University, China.
FAU - Cheng, Wenke
AU  - Cheng W
AD  - School of Life Sciences, Henan University, China.
FAU - Zhu, Renkai
AU  - Zhu R
AD  - School of Life Sciences, Henan University, China.
FAU - Yan, Xinrong
AU  - Yan X
AD  - School of Life Sciences, Henan University, China.
FAU - Yang, Hua
AU  - Yang H
AD  - School of Life Sciences, Henan University, China.
FAU - Liu, Yang
AU  - Liu Y
AD  - School of Life Sciences, Henan University, China.
FAU - Dou, Yu
AU  - Dou Y
AD  - School of Life Sciences, Henan University, China.
FAU - Wang, Wanzhi
AU  - Wang W
AD  - School of Life Sciences, Henan University, China.
FAU - Wang, Jiafu
AU  - Wang J
AD  - School of Life Sciences, Henan University, China; School of Biotechnology, 
      Faculty of Science and Health, Dublin City University, Glasnevin, Dublin 9, 
      Ireland. Electronic address: Jiafu.wang@dcu.ie.
FAU - Meng, Jianghui
AU  - Meng J
AD  - School of Life Sciences, Henan University, China; National Institute for Cellular 
      Biotechnology, Faculty of Science and Health, Dublin City University, Glasnevin, 
      Dublin 9, Ireland. Electronic address: Jianghui.meng@dcu.ie.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210813
PL  - Netherlands
TA  - Brain Behav Immun
JT  - Brain, behavior, and immunity
JID - 8800478
RN  - 0 (Chemokines)
RN  - 0 (Interleukin-13 Receptor alpha2 Subunit)
RN  - 0 (RARRES2 protein, human)
RN  - 0 (Receptors, Interleukin-13)
SB  - IM
MH  - Animals
MH  - Chemokines
MH  - *Dermatitis, Atopic
MH  - Humans
MH  - Immunity, Innate
MH  - Interleukin-13 Receptor alpha2 Subunit
MH  - Keratinocytes
MH  - Mice
MH  - Receptors, Interleukin-13
MH  - Skin
OTO - NOTNLM
OT  - Atopic dermatitis
OT  - IL-13, Cytokine
OT  - IL-13Ralpha1 and 2
OT  - Innate immune
OT  - Toll-like receptor
EDAT- 2021/08/16 06:00
MHDA- 2021/12/15 06:00
CRDT- 2021/08/15 20:37
PHST- 2021/04/09 00:00 [received]
PHST- 2021/08/05 00:00 [revised]
PHST- 2021/08/06 00:00 [accepted]
PHST- 2021/08/16 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/08/15 20:37 [entrez]
AID - S0889-1591(21)00501-8 [pii]
AID - 10.1016/j.bbi.2021.08.211 [doi]
PST - ppublish
SO  - Brain Behav Immun. 2021 Nov;98:28-39. doi: 10.1016/j.bbi.2021.08.211. Epub 2021 
      Aug 13.