title: Muc5b is required for airway defence.
abstract: Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
authors: 1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2].
authors: Michelle G
authors: MG
authors: Roy
authors: 1] University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA [2].
authors: Alessandra
authors: A
authors: Livraghi-Butrico
authors: 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2].
authors: Ashley A
authors: AA
authors: Fletcher
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Melissa M
authors: MM
authors: McElwee
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Scott E
authors: SE
authors: Evans
authors: University of Texas Health Science Center-Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA.
authors: Ryan M
authors: RM
authors: Boerner
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Samantha N
authors: SN
authors: Alexander
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Lindsey K
authors: LK
authors: Bellinghausen
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Alfred S
authors: AS
authors: Song
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Youlia M
authors: YM
authors: Petrova
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Michael J
authors: MJ
authors: Tuvim
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Roberto
authors: R
authors: Adachi
authors: 1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Instituto Tecnológico y de Estudios Superiores de Monterrey, Avenida Eugenio Garza Sada 2501 Sur Colonia Tecnológico, Monterrey, Nuevo León 64849, Mexico.
authors: Irlanda
authors: I
authors: Romo
authors: Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Andrea S
authors: AS
authors: Bordt
authors: 1] Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, Texas 77030, USA [2] University of Houston-Downtown, 1 Main Street, Houston, Texas 77002, USA.
authors: M Gabriela
authors: MG
authors: Bowden
authors: University of Nebraska Medical Center, 985910 Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors: Joseph H
authors: JH
authors: Sisson
authors: University of California San Francisco, 505 Parnassus Avenue, San Francisco, California 27599, USA.
authors: Prescott G
authors: PG
authors: Woodruff
authors: University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors: David J
authors: DJ
authors: Thornton
authors: University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Karine
authors: K
authors: Rousseau
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Maria M
authors: MM
authors: De la Garza
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Seyed J
authors: SJ
authors: Moghaddam
authors: University of Texas Health Science Center-Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA.
authors: Harry
authors: H
authors: Karmouty-Quintana
authors: University of Texas Health Science Center-Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA.
authors: Michael R
authors: MR
authors: Blackburn
authors: University of Texas Health Science Center-Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA.
authors: Scott M
authors: SM
authors: Drouin
authors: University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA.
authors: C William
authors: CW
authors: Davis
authors: University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA.
authors: Kristy A
authors: KA
authors: Terrell
authors: University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA.
authors: Barbara R
authors: BR
authors: Grubb
authors: University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA.
authors: Wanda K
authors: WK
authors: O'Neal
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Sonia C
authors: SC
authors: Flores
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Adela
authors: A
authors: Cota-Gomez
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Catherine A
authors: CA
authors: Lozupone
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Jody M
authors: JM
authors: Donnelly
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Alan M
authors: AM
authors: Watson
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Corinne E
authors: CE
authors: Hennessy
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Rebecca C
authors: RC
authors: Keith
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Ivana V
authors: IV
authors: Yang
authors: 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2] National Jewish Health, Denver, Colorado 80206, USA.
authors: Lea
authors: L
authors: Barthel
authors: 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2] National Jewish Health, Denver, Colorado 80206, USA.
authors: Peter M
authors: PM
authors: Henson
authors: 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2] National Jewish Health, Denver, Colorado 80206, USA.
authors: William J
authors: WJ
authors: Janssen
authors: University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: David A
authors: DA
authors: Schwartz
authors: University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA.
authors: Richard C
authors: RC
authors: Boucher
authors: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors: Burton F
authors: BF
authors: Dickey
authors: 1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.
authors: Christopher M
authors: CM
authors: Evans
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D001424:Bacterial Infections / Q000276:immunology / Q000382:microbiology; D002923:Cilia / Q000502:physiology; D004432:Ear, Middle / Q000276:immunology / Q000382:microbiology; D005260:Female; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D055271:Mucin 5AC / Q000172:deficiency / Q000378:metabolism; D055257:Mucin-5B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000382:microbiology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000276:immunology; D016019:Survival Analysis
chemical_list: C524579:Muc5b protein, mouse; D055271:Mucin 5AC; D055257:Mucin-5B