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

Darin L Wiesner 1 , Richard M Merkhofer 1 , Carole Ober 2 , Gregory C Kujoth 1 , Mengyao Niu 3 , Nancy P Keller 4 , James E Gern 5 , Rebecca A Brockman-Schneider 1 , Michael D Evans 6 , Daniel J Jackson 5 , Thomas Warner 7 , Nizar N Jarjour 8 , Stephane J Esnault 8 , Michael B Feldman 9 , Matthew Freeman 10 , Hongmei Mou 11 , Jatin M Vyas 12 , Bruce S Klein 13

  1. Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA.
  2. Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
  3. Department of Medical Microbiology and Immunology University of Wisconsin-Madison, Madison, WI 53706, USA.
  4. Department of Medical Microbiology and Immunology University of Wisconsin-Madison, Madison, WI 53706, USA; School of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA.
  5. Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
  6. Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN 55455, USA.
  7. Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
  8. Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
  9. Division of Pulmonary and Critical Care Medicine, Harvard Medical School, Boston, MA 02115, USA.
  10. School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
  11. The Mucosal Immunology & Biology Research Center, Harvard Medical School, Boston, MA 02115, USA; Division of Pediatric Pulmonary Medicine, Harvard Medical School, Boston, MA 02115, USA.
  12. Division of Infectious Disease, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  13. Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Medical Microbiology and Immunology University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: bsklein@wisc.edu.

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.

Presented by Darin Wiesner

Immunology & MicrobiologyNicholas Liao2020-04 (Apr)