PMID- 33602818
OWN - NLM
STAT- MEDLINE
DCOM- 20210802
LR  - 20210929
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 118
IP  - 8
DP  - 2021 Feb 23
TI  - Genetic priming of sensory neurons in mice that overexpress PAR2 enhances 
      allergen responsiveness.
LID - 10.1073/pnas.2021386118 [doi]
LID - e2021386118
AB  - Pruritus is a common symptom of inflammatory skin conditions, including atopic 
      dermatitis (AD). Although primary sensory neurons that transmit pruritic signals 
      are well-cataloged, little is known about the neuronal alterations that occur as 
      a result of skin disruption in AD. To address this question, we examined the 
      molecular and behavioral consequences of challenging Grhl3(PAR2/+) mice, which 
      overexpress PAR2 in suprabasal keratinocytes, with serial topical application of 
      the environmental allergen house dust mite (HDM). We monitored behavior and used 
      RNA sequencing, qPCR, and in situ hybridization to evaluate gene expression in 
      trigeminal ganglia (TG), before and after HDM. We found that neither 
      Grhl3(PAR2/+) nor wild-type (WT) mice exhibited spontaneous scratching, and 
      pruritogen-induced acute scratching did not differ. In contrast, HDM exacerbated 
      scratching in Grhl3(PAR2/+) mice. Despite the absence of scratching in untreated 
      Grhl3(PAR2/+) mice, several TG genes in these mice were up-regulated compared to 
      WT. HDM treatment of the Grhl3(PAR2/+) mice enhanced up-regulation of this set of 
      genes and induced additional genes, many within the subset of TG neurons that 
      express TRPV1. The same set of genes was up-regulated in HDM-treated 
      Grhl3(PAR2/+) mice that did not scratch, but at lesser magnitude. Finally, we 
      recorded comparable transcriptional changes in IL31Tg mice, demonstrating that a 
      common genetic program is induced in two AD models. Taken together, we conclude 
      that transcriptional changes that occur in primary sensory neurons in 
      dermatitis-susceptible animals underlie a genetic priming that not only 
      sensitizes the animal to chronic allergens but also contributes to pruritus in 
      atopic skin disease.
FAU - Braz, Joao M
AU  - Braz JM
AUID- ORCID: 0000-0001-8955-0735
AD  - Department of Anatomy, University of California, San Francisco, CA 94158.
FAU - Dembo, Todd
AU  - Dembo T
AD  - Department of Anatomy, University of California, San Francisco, CA 94158.
FAU - Charruyer, Alexandra
AU  - Charruyer A
AD  - Division of Dermatology, San Francisco Veteran's Administration Medical Center, 
      San Francisco, CA 94121.
FAU - Ghadially, Ruby
AU  - Ghadially R
AUID- ORCID: 0000-0002-2880-7987
AD  - Division of Dermatology, San Francisco Veteran's Administration Medical Center, 
      San Francisco, CA 94121.
AD  - Department of Dermatology, University of California, San Francisco, CA 94158.
FAU - Fassett, Marlys S
AU  - Fassett MS
AUID- ORCID: 0000-0002-5750-1928
AD  - Department of Dermatology, University of California, San Francisco, CA 94158.
AD  - Department of Microbiology and Immunology, University of California, San 
      Francisco, CA 94158.
FAU - Basbaum, Allan I
AU  - Basbaum AI
AUID- ORCID: 0000-0002-1710-6333
AD  - Department of Anatomy, University of California, San Francisco, CA 94158; 
      allan.basbaum@ucsf.edu.
LA  - eng
GR  - R01 NS014627/NS/NINDS NIH HHS/United States
GR  - R37 NS014627/NS/NINDS NIH HHS/United States
GR  - I01 BX000794/BX/BLRD VA/United States
GR  - K08 AR074556/AR/NIAMS NIH HHS/United States
GR  - R35 NS097306/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Allergens)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Grhl3 protein, mouse)
RN  - 0 (Receptor, PAR-2)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Allergens/*toxicity
MH  - Animals
MH  - DNA-Binding Proteins/*physiology
MH  - Dermatitis, Atopic/chemically induced/metabolism/*pathology
MH  - Disease Models, Animal
MH  - Mice
MH  - Mice, Transgenic
MH  - RNA-Seq
MH  - Receptor, PAR-2/genetics/*metabolism
MH  - Sensory Receptor Cells/drug effects/metabolism/*pathology
MH  - Skin/drug effects/innervation/metabolism/*pathology
MH  - Transcription Factors/*physiology
PMC - PMC7923356
OTO - NOTNLM
OT  - PAR2
OT  - RNA sequencing
OT  - dermatitis
OT  - itch
OT  - trigeminal neurons
COIS- The authors declare no competing interest.
EDAT- 2021/02/20 06:00
MHDA- 2021/08/03 06:00
PMCR- 2021/08/18
CRDT- 2021/02/19 05:55
PHST- 2021/02/19 05:55 [entrez]
PHST- 2021/02/20 06:00 [pubmed]
PHST- 2021/08/03 06:00 [medline]
PHST- 2021/08/18 00:00 [pmc-release]
AID - 2021386118 [pii]
AID - 202021386 [pii]
AID - 10.1073/pnas.2021386118 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2021 Feb 23;118(8):e2021386118. doi: 
      10.1073/pnas.2021386118.