Human airway smooth muscle promotes human lung mast cell survival, proliferation, and constitutive activation: cooperative roles for CADM1, stem cell factor, and IL-6.
The microlocalization of mast cells within specific tissue compartments is thought to be critical for the pathophysiology of many diverse diseases. This is particularly evident in asthma where they localize to the airway smooth muscle (ASM) bundles. Mast cells are recruited to the ASM by numerous chemoattractants and adhere through CADM1, but the functional consequences of this are unknown. In this study, we show that human ASM maintains human lung mast cell (HLMC) survival in vitro and induces rapid HLMC proliferation. This required cell-cell contact and occurred through a cooperative interaction between membrane-bound stem cell factor (SCF) expressed on ASM, soluble IL-6, and CADM1 expressed on HLMC. There was a physical interaction in HLMC between CADM1 and the SCF receptor (CD117), suggesting that CADM1-dependent adhesion facilitates the interaction of membrane-bound SCF with its receptor. HLMC-ASM coculture also enhanced constitutive HLMC degranulation, revealing a novel smooth muscle-driven allergen-independent mechanism of chronic mast cell activation. Targeting these interactions in asthma might offer a new strategy for the treatment of this common disease.
Hollins
Fay
F
Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester Medical School, United Kingdom.
Kaur
Davinder
D
Yang
Weidong
W
Cruse
Glenn
G
Saunders
Ruth
R
Sutcliffe
Amanda
A
Berger
Patrick
P
Ito
Akihiko
A
Brightling
Christopher E
CE
Bradding
Peter
P
D002448:Cell Adhesion / Q000276:immunology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D002450:Cell Communication / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D008407:Mast Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology / Q000276:immunology*; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019089:Stem Cell Factor / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D015850:Interleukin-6; D008565:Membrane Proteins; D019089:Stem Cell Factor; D025521:Tumor Suppressor Proteins