1. Rachel G. Scheraga, MD Cleveland Clinic Cleveland, OH
The Mechanosensitive TRPV4 Ion Channel Mediates the Pro-resolution/Anti-fibrotic Macrophage Response to LPS
Rachel G. Scheraga, MD
Cleveland Clinic
Cleveland, OH

2. Bacterial pneumonia in Idiopathic pulmonary fibrosis (IPF)
Recurrent pneumonia in IPF patients causes progressive decline in lung function
Infection-associated lung injury leads to edema and inflammatory cell infiltration causing increased matrix stiffness and secretion of cytokines
Molyneaux et al. Am J Respir Crit Care Med, 2014
Murray et al. Nat Rev Immunol , 2001
Wynn et al. Nature, 2013

3. Macrophage phagocytosis
Critical to lung host defense and lung injury, repair, and fibrosis
Requires orchestration of macrophage surface receptors, the particle itself, and extracellular matrix
Rougerie et al. Immunol. Rev, 2013
Wynn et al. Nature, 2013
Blakney et al. J Biomed Mater Res A, 2012

4. Transient receptor potential vanilloid 4 (TRPV4)
Mechanosensitive cation-permeable channel that is activated by chemical and physical stimuli, including plasma membrane stretching
Ubiquitous cell type and tissue expression
Our lab is the first to investigate the significance of TRPV4 in lung fibrosis
Montell et al. Cell, 2002; Everaerts et al; Prog Biophys Mol Biol, 2010

5. Hypothesis
TRPV4 integrates the extracellular matrix stiffness and LPS signals to mediate infection-associated lung injury and repair

6. TRPV4 mediates macrophage phagocytosis of IgG-coated beads
WT-UT
TRPV4 KO-UT
WT-LPS + * * *
TRPV4 KO-LPS
Scheraga et al. J Immunol, In press

7. TRPV4 mediates macrophage phagocytosis of E. coli particles
BMDM AM + + * * * *
Scheraga et al. J Immunol, In press

8. The TRPV4-mediated phagocytic effect depends on matrix stiffness+ + # # # #
Scheraga et al. J Immunol, In press

9. TRPV4 modulates an anti-inflammatory cytokine profile in response to LPS* (% b *
Scheraga et al. J Immunol, In press

10. TRPV4 mediates macrophage phagocytosis of IgG-coated beads in live mice
Saline
LPS WT + * KO
Scheraga et al. J Immunol, In press

11. TRPV4 limits lung injury and initiates resolution in a bacterial pneumonia model
Day 3
Day 8 *
(mg/mL)

12. Conclusions These data suggest :
TRPV4 mediates the phagocytic and cytokine profile response to infection
stiffness-dependent manner
May play a role in progressive fibrosis seen in patients with IPF after infection

13. Acknowledgements Cleveland Clinic - Pathobiology
Dr. Mitchell Olman
Dr. Brian Southern
Dr. Lisa Grove
Susamma Abraham
Kathryn Niese
Cleveland Clinic - Immunology
Dr. Thomas Hamilton
Dr. Chenyang Zhao
Dr. Olman’s Lab

14. Questions?