YAP-mediated mechanotransduction tunes the macrophage inflammatory response

Vijaykumar S Meli; Hamza Atcha; Praveen Krishna Veerasubramanian; Raji R Nagalla; Thuy U Luu; Esther Y Chen; Christian F Guerrero-Juarez; Kosuke Yamaga; William Pandori; Jessica Y Hsieh; Timothy L Downing; David A Fruman; Melissa B Lodoen; Maksim V Plikus; Wenqi Wang; Wendy F Liu

doi:10.1126/sciadv.abb8471

YAP-mediated mechanotransduction tunes the macrophage inflammatory response

Sci Adv. 2020 Dec 4;6(49):eabb8471. doi: 10.1126/sciadv.abb8471. Print 2020 Dec.

Authors

Vijaykumar S Meli^{1

2}, Hamza Atcha^{1

2}, Praveen Krishna Veerasubramanian^{1

2}, Raji R Nagalla^{1

2}, Thuy U Luu^{2

3}, Esther Y Chen^{2

4}, Christian F Guerrero-Juarez^{5

6

7

8

9}, Kosuke Yamaga^{5

6

7

9}, William Pandori^{10

11}, Jessica Y Hsieh^{1

2}, Timothy L Downing^{1

2

6

7

9

12}, David A Fruman^{10

11}, Melissa B Lodoen^{10

11}, Maksim V Plikus^{5

6

7

9}, Wenqi Wang⁵, Wendy F Liu^{13

2

4

11}

Affiliations

¹ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA.
² Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA, USA.
³ Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA, USA.
⁴ Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, USA.
⁵ Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
⁶ NSF-Simons Center for Multiscale Cell Fate Research, University of California, Irvine, Irvine, CA, USA.
⁷ Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
⁸ Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA.
⁹ Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
¹⁰ Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA.
¹¹ Institute for Immunology, University of California, Irvine, Irvine, CA, USA.
¹² Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine, CA, USA.
¹³ Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA. [email protected].

Abstract

Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Extracellular Matrix / metabolism
Humans
Inflammation / metabolism
Macrophages
Mechanotransduction, Cellular* / physiology
YAP-Signaling Proteins*

Substances

YAP-Signaling Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding