The polymeric mucin Muc5ac is required for allergic airway hyperreactivity

Christopher M. Evans; Dorota S. Raclawska; Fani Ttofali; Deborah R. Liptzin; Ashley A. Fletcher; Daniel N. Harper; Maggie A. McGing; Melissa M. McElwee; Olatunji W. Williams; Elizabeth Sanchez; Michelle G. Roy; Kristen N. Kindrachuk; Thomas A. Wynn; Holger K. Eltzschig; Michael R. Blackburn; Michael J. Tuvim; William J. Janssen; David A. Schwartz; Burton F. Dickey

doi:10.1038/ncomms7281

The polymeric mucin Muc5ac is required for allergic airway hyperreactivity

Christopher M. Evans
, Dorota S. Raclawska
, Fani Ttofali
, Deborah R. Liptzin
, Ashley A. Fletcher
, Daniel N. Harper
, Maggie A. McGing
, Melissa M. McElwee
, Olatunji W. Williams
, Elizabeth Sanchez
, Michelle G. Roy
, Kristen N. Kindrachuk
, Thomas A. Wynn
, Holger K. Eltzschig
, Michael R. Blackburn
, Michael J. Tuvim
, William J. Janssen
, David A. Schwartz
, Burton F. Dickey

School of Public and Community Health Sciences

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

250 Scopus citations

Abstract

In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

Original language	English
Article number	6281
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7281
State	Published - Feb 17 2015

Funding

We thank G. Francis, F. Benavides and J. Parker-Thornburg for their assistance in generating mutant and congenic mice. Discussions with Dr W.M. Foster of the Duke University Medical Center were helpful in the design of our aerosol system. This work was supported by the National Institutes of Health Grants R01HL080396 and R21ES023384 (C.M.E.); R21HL120770 (D.A.S.); UH2HL123442 (C.M.E. and D.A.S.); R01HL097000 (B.F.D.); R01HL070952 (M.R.B.); R01DK097075, R01HL092188, R01HL098294 and R01HL119837 (H.K.E.); P01HL114457 (M.R.B. and H.K.E.); R01HL109517 (W.J.J.); and grants by the American Heart Association 14GRNT19990040 (C.M.E.) and the Crohn’s and Colitis Foundation of America (H.K.E.). T.A.W. was supported by the intramural research program at the National Institute of Allergy and Infectious Diseases/National Institutes of Health. Additional support was provided by National Institutes of Health Cancer Center Support Grants P30CA016672 (M.D.

Funders	Funder number
P30CA016672
R01HL070952, R01DK097075, R01HL109517, R01HL119837, R21HL120770, R01HL098294, R21ES023384, R01HL097000, P01HL114457, R01HL080396, R01HL092188
UH2HL123442
American Heart Association	14GRNT19990040

Access to Document

10.1038/ncomms7281

Cite this

Evans, C. M., Raclawska, D. S., Ttofali, F., Liptzin, D. R., Fletcher, A. A., Harper, D. N., McGing, M. A., McElwee, M. M., Williams, O. W., Sanchez, E., Roy, M. G., Kindrachuk, K. N., Wynn, T. A., Eltzschig, H. K., Blackburn, M. R., Tuvim, M. J., Janssen, W. J., Schwartz, D. A., & Dickey, B. F. (2015). The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nature Communications, 6, Article 6281. https://doi.org/10.1038/ncomms7281

@article{26ce42512bec4221ba9f4a69f5394cf6,

title = "The polymeric mucin Muc5ac is required for allergic airway hyperreactivity",

abstract = "In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74\%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.",

author = "Evans, \{Christopher M.\} and Raclawska, \{Dorota S.\} and Fani Ttofali and Liptzin, \{Deborah R.\} and Fletcher, \{Ashley A.\} and Harper, \{Daniel N.\} and McGing, \{Maggie A.\} and McElwee, \{Melissa M.\} and Williams, \{Olatunji W.\} and Elizabeth Sanchez and Roy, \{Michelle G.\} and Kindrachuk, \{Kristen N.\} and Wynn, \{Thomas A.\} and Eltzschig, \{Holger K.\} and Blackburn, \{Michael R.\} and Tuvim, \{Michael J.\} and Janssen, \{William J.\} and Schwartz, \{David A.\} and Dickey, \{Burton F.\}",

note = "Funding Information: We thank G. Francis, F. Benavides and J. Parker-Thornburg for their assistance in generating mutant and congenic mice. Discussions with Dr W.M. Foster of the Duke University Medical Center were helpful in the design of our aerosol system. This work was supported by the National Institutes of Health Grants R01HL080396 and R21ES023384 (C.M.E.); R21HL120770 (D.A.S.); UH2HL123442 (C.M.E. and D.A.S.); R01HL097000 (B.F.D.); R01HL070952 (M.R.B.); R01DK097075, R01HL092188, R01HL098294 and R01HL119837 (H.K.E.); P01HL114457 (M.R.B. and H.K.E.); R01HL109517 (W.J.J.); and grants by the American Heart Association 14GRNT19990040 (C.M.E.) and the Crohn{\textquoteright}s and Colitis Foundation of America (H.K.E.). T.A.W. was supported by the intramural research program at the National Institute of Allergy and Infectious Diseases/National Institutes of Health. Additional support was provided by National Institutes of Health Cancer Center Support Grants P30CA016672 (M.D.",

year = "2015",

month = feb,

day = "17",

doi = "10.1038/ncomms7281",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Evans, CM, Raclawska, DS, Ttofali, F, Liptzin, DR, Fletcher, AA, Harper, DN, McGing, MA, McElwee, MM, Williams, OW, Sanchez, E, Roy, MG, Kindrachuk, KN, Wynn, TA, Eltzschig, HK, Blackburn, MR, Tuvim, MJ, Janssen, WJ, Schwartz, DA & Dickey, BF 2015, 'The polymeric mucin Muc5ac is required for allergic airway hyperreactivity', Nature Communications, vol. 6, 6281. https://doi.org/10.1038/ncomms7281

TY - JOUR

T1 - The polymeric mucin Muc5ac is required for allergic airway hyperreactivity

AU - Evans, Christopher M.

AU - Raclawska, Dorota S.

AU - Ttofali, Fani

AU - Liptzin, Deborah R.

AU - Fletcher, Ashley A.

AU - Harper, Daniel N.

AU - McGing, Maggie A.

AU - McElwee, Melissa M.

AU - Williams, Olatunji W.

AU - Sanchez, Elizabeth

AU - Roy, Michelle G.

AU - Kindrachuk, Kristen N.

AU - Wynn, Thomas A.

AU - Eltzschig, Holger K.

AU - Blackburn, Michael R.

AU - Tuvim, Michael J.

AU - Janssen, William J.

AU - Schwartz, David A.

AU - Dickey, Burton F.

N1 - Funding Information: We thank G. Francis, F. Benavides and J. Parker-Thornburg for their assistance in generating mutant and congenic mice. Discussions with Dr W.M. Foster of the Duke University Medical Center were helpful in the design of our aerosol system. This work was supported by the National Institutes of Health Grants R01HL080396 and R21ES023384 (C.M.E.); R21HL120770 (D.A.S.); UH2HL123442 (C.M.E. and D.A.S.); R01HL097000 (B.F.D.); R01HL070952 (M.R.B.); R01DK097075, R01HL092188, R01HL098294 and R01HL119837 (H.K.E.); P01HL114457 (M.R.B. and H.K.E.); R01HL109517 (W.J.J.); and grants by the American Heart Association 14GRNT19990040 (C.M.E.) and the Crohn’s and Colitis Foundation of America (H.K.E.). T.A.W. was supported by the intramural research program at the National Institute of Allergy and Infectious Diseases/National Institutes of Health. Additional support was provided by National Institutes of Health Cancer Center Support Grants P30CA016672 (M.D.

PY - 2015/2/17

Y1 - 2015/2/17

N2 - In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

AB - In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucous occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

UR - https://www.scopus.com/pages/publications/84923361939

U2 - 10.1038/ncomms7281

DO - 10.1038/ncomms7281

M3 - Article

C2 - 25687754

AN - SCOPUS:84923361939

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6281

ER -

The polymeric mucin Muc5ac is required for allergic airway hyperreactivity

Abstract

Funding

Access to Document

Other files and links

Fingerprint

Cite this