PMID- 37953179
OWN - NLM
STAT- MEDLINE
DCOM- 20231220
LR  - 20231220
IS  - 1873-569X (Electronic)
IS  - 0923-1811 (Linking)
VI  - 112
IP  - 3
DP  - 2023 Dec
TI  - Dual effect of tacrolimus on mast cell-mediated allergy and inflammation through 
      Mas-related G protein-coupled receptor X2.
PG  - 128-137
LID - S0923-1811(23)00226-8 [pii]
LID - 10.1016/j.jdermsci.2023.10.003 [doi]
AB  - BACKGROUND: Topical tacrolimus, although widely used in the treatment of 
      dermatoses, presents with an immediate irritation on initial application 
      resembling a pseudo-allergic reaction. Mas-related G protein-coupled receptor X2 
      (MRGPRX2) in mast cells (MCs) mediates drug-induced pseudo-allergic reaction and 
      immunoglobulin E (IgE)-independent pruritis in chronic skin diseases. However, 
      the immunosuppression mechanism of tacrolimus on MCs via MRGPRX2 has not been 
      reported. OBJECTIVE: To investigate the role of MRGPRX2 and the mechanism of 
      action of tacrolimus on its short-term and long-term applications. METHODS: 
      Wild-type mice, Kit(W-sh/W-sh) mice, and MrgprB2-deficient (MUT) mice were used 
      to study the effect of tacrolimus on in vivo anaphylaxis model. LAD2 cells and 
      MRGPRX2-knockdown LAD2 cells were specifically used to derive the associated 
      mechanism of the tacrolimus effect. RESULTS: Short-term application of tacrolimus 
      triggers IgE-independent activation of MCs via MRGPRX2/B2 in both in vivo and in 
      vitro experiments. Tacrolimus binds to MRGPRX2, which was verified by 
      fluorescently labeled tacrolimus in cells. On long-term treatment with 
      tacrolimus, the initial allergic reaction fades away corresponding with the 
      downregulation of MRGPRX2, which leads to decreased release of inflammatory 
      cytokines (P < 0.05 to P < 0.001). CONCLUSION: Short-term treatment with 
      tacrolimus induces pseudo-allergic reaction via MRGPRX2/B2 in MCs, whereas 
      long-term treatment downregulates expression of MRGPRX2/B2, which may contribute 
      to its potent immunosuppressive effect in the treatment of various skin diseases.
CI  - Copyright (c) 2023 Japanese Society for Investigative Dermatology. Published by 
      Elsevier B.V. All rights reserved.
FAU - Du, Xueshan
AU  - Du X
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Che, Delu
AU  - Che D
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China; Center for Dermatology Disease, Precision Medical 
      Institute, Xi'an, China.
FAU - Peng, Bin
AU  - Peng B
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Zheng, Yi
AU  - Zheng Y
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Hao, Yong
AU  - Hao Y
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China; Department of Dermatology, The Second Affiliated 
      Hospital of Baotou Medical College, Baotou, Inner Mongolia, China.
FAU - Jia, Tao
AU  - Jia T
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Zhang, Xinyue
AU  - Zhang X
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China.
FAU - Geng, Songmei
AU  - Geng S
AD  - Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong 
      University, Xi'an, China; Center for Dermatology Disease, Precision Medical 
      Institute, Xi'an, China. Electronic address: gsm312@yahoo.com.
LA  - eng
PT  - Journal Article
DEP - 20231017
PL  - Netherlands
TA  - J Dermatol Sci
JT  - Journal of dermatological science
JID - 9011485
RN  - WM0HAQ4WNM (Tacrolimus)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Receptors, Neuropeptide)
RN  - Congenital disorder of glycosylation, type 2C
SB  - IM
MH  - Animals
MH  - Mice
MH  - Tacrolimus/adverse effects
MH  - Mast Cells
MH  - *Hypersensitivity, Delayed
MH  - *Anaphylaxis/chemically induced/metabolism
MH  - Inflammation/metabolism
MH  - Immunoglobulin E
MH  - Receptors, G-Protein-Coupled/metabolism
MH  - *Skin Diseases/metabolism
MH  - Receptors, Neuropeptide/metabolism
MH  - Cell Degranulation
OTO - NOTNLM
OT  - Inflammation
OT  - Itching
OT  - MRGPRX2/B2
OT  - Mast cell
OT  - Tacrolimus
COIS- Conflict of Interest The authors have no conflict of interest to declare.
EDAT- 2023/11/13 00:42
MHDA- 2023/12/20 06:42
CRDT- 2023/11/12 21:56
PHST- 2023/04/13 00:00 [received]
PHST- 2023/10/09 00:00 [revised]
PHST- 2023/10/16 00:00 [accepted]
PHST- 2023/12/20 06:42 [medline]
PHST- 2023/11/13 00:42 [pubmed]
PHST- 2023/11/12 21:56 [entrez]
AID - S0923-1811(23)00226-8 [pii]
AID - 10.1016/j.jdermsci.2023.10.003 [doi]
PST - ppublish
SO  - J Dermatol Sci. 2023 Dec;112(3):128-137. doi: 10.1016/j.jdermsci.2023.10.003. 
      Epub 2023 Oct 17.