Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation

Darin L. Wiesner; Richard M. Merkhofer; Carole Ober; Gregory C. Kujoth; Mengyao Niu; Nancy P. Keller; James E. Gern; Rebecca A. Brockman-Schneider; Michael D. Evans; Daniel J. Jackson; Thomas Warner; Nizar N. Jarjour; Stephane J. Esnault; Michael B. Feldman; Matthew Freeman; Hongmei Mou; Jatin M. Vyas; Bruce S. Klein

doi:10.1016/j.chom.2020.02.006

Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation

Darin L. Wiesner, Richard M. Merkhofer, Carole Ober, Gregory C. Kujoth, Mengyao Niu, Nancy P. Keller, James E. Gern, Rebecca A. Brockman-Schneider, Michael D. Evans, Daniel J. Jackson, Thomas Warner, Nizar N. Jarjour, Stephane J. Esnault, Michael B. Feldman, Matthew Freeman, Hongmei Mou, Jatin M. Vyas, Bruce S. Klein

CTSI Biostatistics

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Airway epithelium is the first body surface to contact inhaled irritants and report danger. Here, we report how epithelial cells recognize and respond to aeroallergen alkaline protease 1 (Alp1) of Aspergillus sp., because proteases are critical components of many allergens that provoke asthma. In a murine model, Alp1 elicits helper T (Th) cell-dependent lung eosinophilia that is initiated by the rapid response of bronchiolar club cells to Alp1. Alp1 damages bronchiolar cell junctions, which triggers a calcium flux signaled through calcineurin within club cells of the bronchioles, inciting inflammation. In two human cohorts, we link fungal sensitization and/or asthma with SNP/protein expression of the mechanosensitive calcium channel, TRPV4. TRPV4 is also necessary and sufficient for club cells to sensitize mice to Alp1. Thus, club cells detect junction damage as mechanical stress, which signals danger via TRPV4, calcium, and calcineurin to initiate allergic sensitization.

Original language	English (US)
Pages (from-to)	614-628.e6
Journal	Cell Host and Microbe
Volume	27
Issue number	4
DOIs	https://doi.org/10.1016/j.chom.2020.02.006
State	Published - Apr 8 2020

Bibliographical note

Funding Information:
We thank UW-Madison core facilities: Carbone Cancer Center (NIH P30 CA014520, 1S100OD018202-01), Biotechnology Center (NIH P50 GM64598, R33 DK070297; NSF DBI-0520825, DBI-9977525) Biochemistry Optical Core (Elle Gresvald), and Translational Research Initiatives in Pathology (Toshi Kinoshita). Robert Gordon (Pediatrics, UW-Madison) assisted with graphic design. Postdoctoral fellowship support included the Hartwell Foundation and NHLBI T32 HL07899 (D.L.W.), and NHLBI T32 HL116275 (M.B.F.). Research grant support included NIH R01 AI130411 (B.S.K); PO1 HL70381 and UL1 TR000427 (D.J.J. J.E.G. R.A.B.-S. and C.O. in support of COAST [Childhood Origins of Asthma]); R01AI136529 (J.M.V.); and Cystic Fibrosis Foundation Research Grant MOU19G0 and Charles H. Hood Foundation Child Health Research Awards Program (H.M.). Wolfgang Von Liedkle (Duke University) provided TRPV4-floxed mice. Hartmut Weiler (Blood Center of Wisconsin and Medical College of Wisconsin) provided PAR1?/? mice. D.L.W. conceived, designed and performed experiments, and drafted the manuscript. S.J.E. and N.N.J. prepared bronchial biopsies. M.N. and N.P.K. assisted with design and execution of experiments related to Aspergillus culture supernates. R.A.B.-S. and J.E.G. provided ciliated cells grown at air-liquid interface. M.B.F. and J.M.V. prepared club cells. D.J.J. M.D.E. and C.O. collected data from COAST patients, analyzed the data, and assisted in writing the manuscript. T.W. analyzed histology of bronchial tissue biopsies. R.M.M. and G.C.K. assisted with analysis of TRPV4 genotype and SNP analysis. B.S.K assisted with study concept, design, and execution and helped write the manuscript. M.B.F. is an employee of Vertex Pharmaceuticals and may own stock in that company. All other authors declare no competing interests.

Funding Information:
We thank UW-Madison core facilities: Carbone Cancer Center ( NIH P30 CA014520 , 1S100OD018202-01 ), Biotechnology Center ( NIH P50 GM64598 , R33 DK070297 ; NSF DBI-0520825 , DBI-9977525 ) Biochemistry Optical Core (Elle Gresvald), and Translational Research Initiatives in Pathology (Toshi Kinoshita). Robert Gordon (Pediatrics, UW-Madison) assisted with graphic design. Postdoctoral fellowship support included the Hartwell Foundation and NHLBI T32 HL07899 (D.L.W.), and NHLBI T32 HL116275 (M.B.F.). Research grant support included NIH R01 AI130411 (B.S.K); PO1 HL70381 and UL1 TR000427 (D.J.J., J.E.G., R.A.B.-S., and C.O. in support of COAST [Childhood Origins of Asthma]); R01AI136529 (J.M.V.); and Cystic Fibrosis Foundation Research Grant MOU19G0 and Charles H. Hood Foundation Child Health Research Awards Program (H.M.). Wolfgang Von Liedkle (Duke University) provided TRPV4-floxed mice. Hartmut Weiler (Blood Center of Wisconsin and Medical College of Wisconsin) provided PAR1 −/− mice.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

Aspergillus
TRPV4
alkaline protease 1
asthma
calcineurin
calcium
club cells

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10.1016/j.chom.2020.02.006

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Wiesner, D. L., Merkhofer, R. M., Ober, C., Kujoth, G. C., Niu, M., Keller, N. P., Gern, J. E., Brockman-Schneider, R. A., Evans, M. D., Jackson, D. J., Warner, T., Jarjour, N. N., Esnault, S. J., Feldman, M. B., Freeman, M., Mou, H., Vyas, J. M., & Klein, B. S. (2020). Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation. Cell Host and Microbe, 27(4), 614-628.e6. https://doi.org/10.1016/j.chom.2020.02.006

Wiesner, DL, Merkhofer, RM, Ober, C, Kujoth, GC, Niu, M, Keller, NP, Gern, JE, Brockman-Schneider, RA, Evans, MD, Jackson, DJ, Warner, T, Jarjour, NN, Esnault, SJ, Feldman, MB, Freeman, M, Mou, H, Vyas, JM & Klein, BS 2020, 'Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation', Cell Host and Microbe, vol. 27, no. 4, pp. 614-628.e6. https://doi.org/10.1016/j.chom.2020.02.006

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title = "Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation",

abstract = "Airway epithelium is the first body surface to contact inhaled irritants and report danger. Here, we report how epithelial cells recognize and respond to aeroallergen alkaline protease 1 (Alp1) of Aspergillus sp., because proteases are critical components of many allergens that provoke asthma. In a murine model, Alp1 elicits helper T (Th) cell-dependent lung eosinophilia that is initiated by the rapid response of bronchiolar club cells to Alp1. Alp1 damages bronchiolar cell junctions, which triggers a calcium flux signaled through calcineurin within club cells of the bronchioles, inciting inflammation. In two human cohorts, we link fungal sensitization and/or asthma with SNP/protein expression of the mechanosensitive calcium channel, TRPV4. TRPV4 is also necessary and sufficient for club cells to sensitize mice to Alp1. Thus, club cells detect junction damage as mechanical stress, which signals danger via TRPV4, calcium, and calcineurin to initiate allergic sensitization.",

keywords = "Aspergillus, TRPV4, alkaline protease 1, asthma, calcineurin, calcium, club cells",

author = "Wiesner, {Darin L.} and Merkhofer, {Richard M.} and Carole Ober and Kujoth, {Gregory C.} and Mengyao Niu and Keller, {Nancy P.} and Gern, {James E.} and Brockman-Schneider, {Rebecca A.} and Evans, {Michael D.} and Jackson, {Daniel J.} and Thomas Warner and Jarjour, {Nizar N.} and Esnault, {Stephane J.} and Feldman, {Michael B.} and Matthew Freeman and Hongmei Mou and Vyas, {Jatin M.} and Klein, {Bruce S.}",

note = "Funding Information: We thank UW-Madison core facilities: Carbone Cancer Center (NIH P30 CA014520, 1S100OD018202-01), Biotechnology Center (NIH P50 GM64598, R33 DK070297; NSF DBI-0520825, DBI-9977525) Biochemistry Optical Core (Elle Gresvald), and Translational Research Initiatives in Pathology (Toshi Kinoshita). Robert Gordon (Pediatrics, UW-Madison) assisted with graphic design. Postdoctoral fellowship support included the Hartwell Foundation and NHLBI T32 HL07899 (D.L.W.), and NHLBI T32 HL116275 (M.B.F.). Research grant support included NIH R01 AI130411 (B.S.K); PO1 HL70381 and UL1 TR000427 (D.J.J. J.E.G. R.A.B.-S. and C.O. in support of COAST [Childhood Origins of Asthma]); R01AI136529 (J.M.V.); and Cystic Fibrosis Foundation Research Grant MOU19G0 and Charles H. Hood Foundation Child Health Research Awards Program (H.M.). Wolfgang Von Liedkle (Duke University) provided TRPV4-floxed mice. Hartmut Weiler (Blood Center of Wisconsin and Medical College of Wisconsin) provided PAR1?/? mice. D.L.W. conceived, designed and performed experiments, and drafted the manuscript. S.J.E. and N.N.J. prepared bronchial biopsies. M.N. and N.P.K. assisted with design and execution of experiments related to Aspergillus culture supernates. R.A.B.-S. and J.E.G. provided ciliated cells grown at air-liquid interface. M.B.F. and J.M.V. prepared club cells. D.J.J. M.D.E. and C.O. collected data from COAST patients, analyzed the data, and assisted in writing the manuscript. T.W. analyzed histology of bronchial tissue biopsies. R.M.M. and G.C.K. assisted with analysis of TRPV4 genotype and SNP analysis. B.S.K assisted with study concept, design, and execution and helped write the manuscript. M.B.F. is an employee of Vertex Pharmaceuticals and may own stock in that company. All other authors declare no competing interests. Funding Information: We thank UW-Madison core facilities: Carbone Cancer Center ( NIH P30 CA014520 , 1S100OD018202-01 ), Biotechnology Center ( NIH P50 GM64598 , R33 DK070297 ; NSF DBI-0520825 , DBI-9977525 ) Biochemistry Optical Core (Elle Gresvald), and Translational Research Initiatives in Pathology (Toshi Kinoshita). Robert Gordon (Pediatrics, UW-Madison) assisted with graphic design. Postdoctoral fellowship support included the Hartwell Foundation and NHLBI T32 HL07899 (D.L.W.), and NHLBI T32 HL116275 (M.B.F.). Research grant support included NIH R01 AI130411 (B.S.K); PO1 HL70381 and UL1 TR000427 (D.J.J., J.E.G., R.A.B.-S., and C.O. in support of COAST [Childhood Origins of Asthma]); R01AI136529 (J.M.V.); and Cystic Fibrosis Foundation Research Grant MOU19G0 and Charles H. Hood Foundation Child Health Research Awards Program (H.M.). Wolfgang Von Liedkle (Duke University) provided TRPV4-floxed mice. Hartmut Weiler (Blood Center of Wisconsin and Medical College of Wisconsin) provided PAR1 −/− mice. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

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day = "8",

doi = "10.1016/j.chom.2020.02.006",

language = "English (US)",

volume = "27",

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T1 - Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation

AU - Wiesner, Darin L.

AU - Merkhofer, Richard M.

AU - Ober, Carole

AU - Kujoth, Gregory C.

AU - Niu, Mengyao

AU - Keller, Nancy P.

AU - Gern, James E.

AU - Brockman-Schneider, Rebecca A.

AU - Evans, Michael D.

AU - Jackson, Daniel J.

AU - Warner, Thomas

AU - Jarjour, Nizar N.

AU - Esnault, Stephane J.

AU - Feldman, Michael B.

AU - Freeman, Matthew

AU - Mou, Hongmei

AU - Vyas, Jatin M.

AU - Klein, Bruce S.

N1 - Funding Information: We thank UW-Madison core facilities: Carbone Cancer Center (NIH P30 CA014520, 1S100OD018202-01), Biotechnology Center (NIH P50 GM64598, R33 DK070297; NSF DBI-0520825, DBI-9977525) Biochemistry Optical Core (Elle Gresvald), and Translational Research Initiatives in Pathology (Toshi Kinoshita). Robert Gordon (Pediatrics, UW-Madison) assisted with graphic design. Postdoctoral fellowship support included the Hartwell Foundation and NHLBI T32 HL07899 (D.L.W.), and NHLBI T32 HL116275 (M.B.F.). Research grant support included NIH R01 AI130411 (B.S.K); PO1 HL70381 and UL1 TR000427 (D.J.J. J.E.G. R.A.B.-S. and C.O. in support of COAST [Childhood Origins of Asthma]); R01AI136529 (J.M.V.); and Cystic Fibrosis Foundation Research Grant MOU19G0 and Charles H. Hood Foundation Child Health Research Awards Program (H.M.). Wolfgang Von Liedkle (Duke University) provided TRPV4-floxed mice. Hartmut Weiler (Blood Center of Wisconsin and Medical College of Wisconsin) provided PAR1?/? mice. D.L.W. conceived, designed and performed experiments, and drafted the manuscript. S.J.E. and N.N.J. prepared bronchial biopsies. M.N. and N.P.K. assisted with design and execution of experiments related to Aspergillus culture supernates. R.A.B.-S. and J.E.G. provided ciliated cells grown at air-liquid interface. M.B.F. and J.M.V. prepared club cells. D.J.J. M.D.E. and C.O. collected data from COAST patients, analyzed the data, and assisted in writing the manuscript. T.W. analyzed histology of bronchial tissue biopsies. R.M.M. and G.C.K. assisted with analysis of TRPV4 genotype and SNP analysis. B.S.K assisted with study concept, design, and execution and helped write the manuscript. M.B.F. is an employee of Vertex Pharmaceuticals and may own stock in that company. All other authors declare no competing interests. Funding Information: We thank UW-Madison core facilities: Carbone Cancer Center ( NIH P30 CA014520 , 1S100OD018202-01 ), Biotechnology Center ( NIH P50 GM64598 , R33 DK070297 ; NSF DBI-0520825 , DBI-9977525 ) Biochemistry Optical Core (Elle Gresvald), and Translational Research Initiatives in Pathology (Toshi Kinoshita). Robert Gordon (Pediatrics, UW-Madison) assisted with graphic design. Postdoctoral fellowship support included the Hartwell Foundation and NHLBI T32 HL07899 (D.L.W.), and NHLBI T32 HL116275 (M.B.F.). Research grant support included NIH R01 AI130411 (B.S.K); PO1 HL70381 and UL1 TR000427 (D.J.J., J.E.G., R.A.B.-S., and C.O. in support of COAST [Childhood Origins of Asthma]); R01AI136529 (J.M.V.); and Cystic Fibrosis Foundation Research Grant MOU19G0 and Charles H. Hood Foundation Child Health Research Awards Program (H.M.). Wolfgang Von Liedkle (Duke University) provided TRPV4-floxed mice. Hartmut Weiler (Blood Center of Wisconsin and Medical College of Wisconsin) provided PAR1 −/− mice. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/4/8

Y1 - 2020/4/8

N2 - Airway epithelium is the first body surface to contact inhaled irritants and report danger. Here, we report how epithelial cells recognize and respond to aeroallergen alkaline protease 1 (Alp1) of Aspergillus sp., because proteases are critical components of many allergens that provoke asthma. In a murine model, Alp1 elicits helper T (Th) cell-dependent lung eosinophilia that is initiated by the rapid response of bronchiolar club cells to Alp1. Alp1 damages bronchiolar cell junctions, which triggers a calcium flux signaled through calcineurin within club cells of the bronchioles, inciting inflammation. In two human cohorts, we link fungal sensitization and/or asthma with SNP/protein expression of the mechanosensitive calcium channel, TRPV4. TRPV4 is also necessary and sufficient for club cells to sensitize mice to Alp1. Thus, club cells detect junction damage as mechanical stress, which signals danger via TRPV4, calcium, and calcineurin to initiate allergic sensitization.

AB - Airway epithelium is the first body surface to contact inhaled irritants and report danger. Here, we report how epithelial cells recognize and respond to aeroallergen alkaline protease 1 (Alp1) of Aspergillus sp., because proteases are critical components of many allergens that provoke asthma. In a murine model, Alp1 elicits helper T (Th) cell-dependent lung eosinophilia that is initiated by the rapid response of bronchiolar club cells to Alp1. Alp1 damages bronchiolar cell junctions, which triggers a calcium flux signaled through calcineurin within club cells of the bronchioles, inciting inflammation. In two human cohorts, we link fungal sensitization and/or asthma with SNP/protein expression of the mechanosensitive calcium channel, TRPV4. TRPV4 is also necessary and sufficient for club cells to sensitize mice to Alp1. Thus, club cells detect junction damage as mechanical stress, which signals danger via TRPV4, calcium, and calcineurin to initiate allergic sensitization.

KW - Aspergillus

KW - TRPV4

KW - alkaline protease 1

KW - asthma

KW - calcineurin

KW - calcium

KW - club cells

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JO - Cell Host and Microbe

JF - Cell Host and Microbe

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ER -

Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation

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