Induction of a homeostatic circuit in lung tissue by microbial compounds.
TGFbeta presented and activated by integrin alphavbeta6 expressed on alveolar epithelial cells (AEC) continuously inhibits the functionality of alveolar macrophages (AM). Despite this inhibition, AM retain their ability to respond to inhaled microorganisms. Herein we describe a homeostatic circuit through which the effects of microbial products on macrophages transiently circumvent this inhibition by repressing alphavbeta6 expression on AEC. Subsequent production of matrix metalloproteinases by activated AM activates latent TGFbeta, reinduces alphavbeta6 expression, and thereby reinstates tonic inhibition of AM function. Our results reveal how AM can be activated while minimizing their potential to inflict collateral damage to the adjacent lung tissue and indicate that tissue-specific microenvironmental factors shape organ-specific defense strategies against microbial invasion.
Takabayshi
Kenji
K
Department of Medicine, University of California, San Diego, La Jolla, 92093, USA.
Corr
Maripat
M
Hayashi
Tomoko
T
Redecke
Vanessa
V
Beck
Lucinda
L
Guiney
Donald
D
Sheppard
Dean
D
Raz
Eyal
E
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D001424:Bacterial Infections / Q000276:immunology*; D015153:Blotting, Western; D002450:Cell Communication / Q000276:immunology*; D005260:Female; D006706:Homeostasis / Q000276:immunology*; D016023:Integrins / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D016676:Macrophages, Alveolar / Q000276:immunology*; D020782:Matrix Metalloproteinases / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020239:Receptor Cross-Talk / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology / Q000382:microbiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism
D000951:Antigens, Neoplasm; D016023:Integrins; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D020782:Matrix Metalloproteinases