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PNAS 110 (2): 660-665

Copyright © 2013 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

Makoto Kudoa,b, S. M. Amin Khalifeh Soltanic,d, Stephen A. Sakumac,d, William McKleroyc,d, Ting-Hein Leec,d, Prescott G. Woodruffd, Jae Woo Leee, Katherine Huanga,d, Chun Chena,d, Mehrdad Arjomandia,f, Xiaozhu Huanga,d, and Kamran Atabaia,c,d,1

aLung Biology Center, University of California, San Francisco, CA 94143; bDepartment of Internal Medicine and Clinical Immunology, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan; cCardiovascular Research Institute, University of California, San Francisco, CA 94143; dDepartment of Medicine, University of California, San Francisco, CA 94143; eDepartment of Anesthesia, University of California, San Francisco, CA 94143; and fPulmonary Research Group, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121;

Edited by Paul Anderson, Brigham and Women’s Hospital, Boston, MA, and accepted by the Editorial Board November 29, 2012 (received for review September 24, 2012)

Abstract: Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8–/–) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8–/– ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13–induced NF-{kappa}B activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.

Key Words: calcium sensitivity • lactadherin

Author contributions: M.K. and K.A. designed research; M.K., S.M.A.K.S., S.A.S., W.M., K.H., C.C., X.H., and K.A. performed research; P.G.W., J.W.L., and M.A. contributed new reagents/analytic tools; M.K., S.A.S., T.-H.L., C.C., X.H., and K.A. analyzed data; and M.K., W.M., and K.A. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission. P.A. is a guest editor invited by the Editorial Board.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1216673110/-/DCSupplemental.

1To whom correspondence should be addressed. E-mail: kamran.atabai{at}ucsf.edu.

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