Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43

Y. Imoto, Atsushi Kato, T. Takabayashi, M. Sakashita, J. E. Norton, L. A. Suh, R. G. Carter, A. R. Weibman, Kathryn E Hulse, Whitney Stevens, K. E. Harris, Anju Tripathi Peters, Leslie C Grammer III, Bruce Kuang-Huay Tan, Kevin Christian Welch, David B Conley Jr, Robert C Kern, S. Fujieda, Robert P Schleimer*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. Objective: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. Methods: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. Results: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. Conclusions and Clinical Relevance: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

Original languageEnglish (US)
Pages (from-to)544-554
Number of pages11
JournalClinical and Experimental Allergy
Volume48
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Volatile Fatty Acids
Tissue Plasminogen Activator
Epithelial Cells
Nasal Polyps
Gene Silencing
Fibrin
Immunohistochemistry
Butyric Acid
G-Protein-Coupled Receptors
Nose
Nonesterified Fatty Acids
Acetic Acid
Small Interfering RNA
Chronic Disease
Down-Regulation
Epithelium
Messenger RNA

Keywords

  • GPR41
  • GPR43
  • chronic rhinosinusitis
  • fibrin
  • t-PA

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{3a8f9311a69a415e9159e2df26f10320,
title = "Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43",
abstract = "Background: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. Objective: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. Methods: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. Results: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. Conclusions and Clinical Relevance: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.",
keywords = "GPR41, GPR43, chronic rhinosinusitis, fibrin, t-PA",
author = "Y. Imoto and Atsushi Kato and T. Takabayashi and M. Sakashita and Norton, {J. E.} and Suh, {L. A.} and Carter, {R. G.} and Weibman, {A. R.} and Hulse, {Kathryn E} and Whitney Stevens and Harris, {K. E.} and Peters, {Anju Tripathi} and {Grammer III}, {Leslie C} and Tan, {Bruce Kuang-Huay} and Welch, {Kevin Christian} and {Conley Jr}, {David B} and Kern, {Robert C} and S. Fujieda and Schleimer, {Robert P}",
year = "2018",
month = "5",
day = "1",
doi = "10.1111/cea.13119",
language = "English (US)",
volume = "48",
pages = "544--554",
journal = "Clinical and Experimental Allergy",
issn = "0954-7894",
publisher = "Wiley-Blackwell",
number = "5",

}

Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43. / Imoto, Y.; Kato, Atsushi; Takabayashi, T.; Sakashita, M.; Norton, J. E.; Suh, L. A.; Carter, R. G.; Weibman, A. R.; Hulse, Kathryn E; Stevens, Whitney; Harris, K. E.; Peters, Anju Tripathi; Grammer III, Leslie C; Tan, Bruce Kuang-Huay; Welch, Kevin Christian; Conley Jr, David B; Kern, Robert C; Fujieda, S.; Schleimer, Robert P.

In: Clinical and Experimental Allergy, Vol. 48, No. 5, 01.05.2018, p. 544-554.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43

AU - Imoto, Y.

AU - Kato, Atsushi

AU - Takabayashi, T.

AU - Sakashita, M.

AU - Norton, J. E.

AU - Suh, L. A.

AU - Carter, R. G.

AU - Weibman, A. R.

AU - Hulse, Kathryn E

AU - Stevens, Whitney

AU - Harris, K. E.

AU - Peters, Anju Tripathi

AU - Grammer III, Leslie C

AU - Tan, Bruce Kuang-Huay

AU - Welch, Kevin Christian

AU - Conley Jr, David B

AU - Kern, Robert C

AU - Fujieda, S.

AU - Schleimer, Robert P

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Background: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. Objective: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. Methods: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. Results: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. Conclusions and Clinical Relevance: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

AB - Background: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. Objective: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. Methods: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. Results: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. Conclusions and Clinical Relevance: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

KW - GPR41

KW - GPR43

KW - chronic rhinosinusitis

KW - fibrin

KW - t-PA

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U2 - 10.1111/cea.13119

DO - 10.1111/cea.13119

M3 - Article

VL - 48

SP - 544

EP - 554

JO - Clinical and Experimental Allergy

JF - Clinical and Experimental Allergy

SN - 0954-7894

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