PMID- 38422887
OWN - NLM
STAT- MEDLINE
DCOM- 20240313
LR  - 20240314
IS  - 1872-9142 (Electronic)
IS  - 0161-5890 (Linking)
VI  - 168
DP  - 2024 Apr
TI  - Silencing of forkhead box C1 reduces nasal epithelial barrier damage in mice with 
      allergic rhinitis via epigenetically upregulating secreted frizzled-related 
      protein 5.
PG  - 51-63
LID - S0161-5890(24)00037-3 [pii]
LID - 10.1016/j.molimm.2024.02.011 [doi]
AB  - Allergic rhinitis (AR) is caused by immunoglobulin E (IgE)-mediated reactions to 
      inhaled allergens, which leads to mucosal inflammation and barrier dysfunction. 
      The transcription factor forkhead box C1 (FOXC1) has been identified to be 
      associated with allergic inflammation. This study sought to uncover the role of 
      FOXC1 in AR. A murine model of AR was induced by repeated intranasal ovalbumin 
      (OVA) challenges. Results revealed that high FOXC1 expression was found in the 
      nasal mucosal epithelium of AR mice. Nasal allergy symptoms, mucosal epithelial 
      swelling, goblet cell hyperplasia and eosinophil infiltration in AR mice were 
      attenuated after silencing of FOXC1. Knockdown of FOXC1 decreased the levels of 
      T-helper 2 cytokines interleukin(IL)-4 and IL-13 in nasal lavage fluid, and serum 
      OVA-specific IgE and histamine. Silencing of FOXC1 restored nasal epithelial 
      integrity in AR mice by enhancing the expression of tight junctions (TJs) and 
      adherence junction. Furthermore, knocking down FOXC1 increased tight junction 
      expression and transepithelial electrical resistance (TEER) in IL-13-treated 
      air-liquid interface (ALI) cultures of human nasal epithelial cells (HNEpCs). 
      Mechanistically, silencing of FOXC1 induced DNA methylation of secreted 
      frizzled-related protein 5 (SFRP5) promoter and increased its expression in the 
      nasal mucosa of AR mice and IL-13-treated ALI cultures. FOXC1 overexpression 
      transcriptionally activated DNA methyltransferase 3B (DNMT3B) in IL-13-treated 
      ALI cultures. Knockdown of SFRP5 reversed the protection of FOXC1 silencing on 
      epithelial barrier damage induced by IL-13. Collectively, silencing of FOXC1 
      reduced allergic inflammation and nasal epithelial barrier damage in AR mice via 
      upregulating SFRP5, which may be attribute to DNMT3B-driven DNA methylation. Our 
      study indicated that FOXC1 may represent a potential therapeutic target for AR.
CI  - Copyright (c) 2024 Elsevier Ltd. All rights reserved.
FAU - Shi, Zhaohui
AU  - Shi Z
AD  - Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital & 
      Shenzhen Otolaryngology Research Institute, Shenzhen 518172, Guangdong, China; 
      Department of Otorhinolaryngology-Head and Neck Surgery, Department of Allergy, 
      Naso-Orbital-Maxilla and Skull Base Center, The Third Affiliated Hospital of Sun 
      Yat-sen University, Guangzhou 510630, Guangdong, China. Electronic address: 
      shizhh35@mail.sysu.edu.cn.
FAU - Zhao, Tianfeng
AU  - Zhao T
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, The First Affiliated 
      Hospital of AFMU (Xijing Hospital), Air force Medical University, Xi'an 710032, 
      Shaanxi , China.
FAU - Li, Dingbo
AU  - Li D
AD  - Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital & 
      Shenzhen Otolaryngology Research Institute, Shenzhen 518172, Guangdong, China.
FAU - Wang, Chong
AU  - Wang C
AD  - Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital & 
      Shenzhen Otolaryngology Research Institute, Shenzhen 518172, Guangdong, China.
FAU - Luo, Yanjie
AU  - Luo Y
AD  - Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital & 
      Shenzhen Otolaryngology Research Institute, Shenzhen 518172, Guangdong, China; 
      Department of Otorhinolaryngology-Head and Neck Surgery, Department of Allergy, 
      Naso-Orbital-Maxilla and Skull Base Center, The Third Affiliated Hospital of Sun 
      Yat-sen University, Guangzhou 510630, Guangdong, China.
FAU - Zheng, Yangshan
AU  - Zheng Y
AD  - Department of Otolaryngology, Shenzhen Longgang Otolaryngology Hospital & 
      Shenzhen Otolaryngology Research Institute, Shenzhen 518172, Guangdong, China.
LA  - eng
PT  - Journal Article
DEP - 20240229
PL  - England
TA  - Mol Immunol
JT  - Molecular immunology
JID - 7905289
RN  - 0 (Cytokines)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - 0 (Interleukin-13)
RN  - 9006-59-1 (Ovalbumin)
RN  - 0 (Secreted Frizzled-Related Proteins)
RN  - 0 (Sfrp5 protein, mouse)
RN  - 0 (Foxc1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Immunoglobulin E/metabolism
MH  - Inflammation/metabolism
MH  - Interleukin-13/metabolism
MH  - Mice, Inbred BALB C
MH  - Nasal Mucosa/metabolism
MH  - Ovalbumin/metabolism
MH  - *Rhinitis, Allergic/genetics/drug therapy
MH  - *Secreted Frizzled-Related Proteins
OTO - NOTNLM
OT  - Allergic rhinitis
OT  - DNA methylation
OT  - Forkhead box C1
OT  - Nasal epithelial barrier integrity
OT  - Secreted frizzled-related protein 5
COIS- Declaration of Competing Interest The authors declare that they have no competing 
      interests.
EDAT- 2024/03/01 01:22
MHDA- 2024/03/13 06:46
CRDT- 2024/02/29 18:14
PHST- 2023/11/02 00:00 [received]
PHST- 2024/02/04 00:00 [revised]
PHST- 2024/02/13 00:00 [accepted]
PHST- 2024/03/13 06:46 [medline]
PHST- 2024/03/01 01:22 [pubmed]
PHST- 2024/02/29 18:14 [entrez]
AID - S0161-5890(24)00037-3 [pii]
AID - 10.1016/j.molimm.2024.02.011 [doi]
PST - ppublish
SO  - Mol Immunol. 2024 Apr;168:51-63. doi: 10.1016/j.molimm.2024.02.011. Epub 2024 Feb 
      29.