Double deficiency of tetraspanins CD9 and CD81 alters cell motility and protease production of macrophages and causes chronic obstructive pulmonary disease-like phenotype in mice.
CD9 and CD81 are closely related tetraspanins that regulate cell motility and signaling by facilitating the organization of multimolecular membrane complexes, including integrins. We show that CD9 and CD81 are down-regulated in smoking-related inflammatory response of a macrophage line, RAW264.7. When functions of CD9 and CD81 were ablated with monoclonal antibody treatment, small interfering RNA transfection, or gene knock-out, macrophages were less motile and produced larger amounts of matrix metalloproteinase (MMP)-2 and MMP-9 than control cells in vitro. In line with this, CD9/CD81 double-knock-out mice spontaneously developed pulmonary emphysema, a major pathological component of chronic obstructive pulmonary disease (COPD). The mutant lung contained an increased number of alveolar macrophages with elevated activities of MMP-2 and MMP-9 and progressively displayed enlarged airspace and disruption of elastic fibers in the alveoli. Secretory cell metaplasia, a finding similar to goblet cell metaplasia in cigarette smokers, was also observed in the epithelium of terminal bronchioles. With aging, the double-knockout mice showed extrapulmonary phenotypes, including weight loss, kyphosis, and osteopenia. These results suggest that the tetraspanins CD9 and CD81 regulate cell motility and protease production of macrophages and that their dysfunction may underlie the progression of COPD.
Takeda
Yoshito
Y
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
He
Ping
P
Tachibana
Isao
I
Zhou
Bo
B
Miyado
Kenji
K
Kaneko
Hideshi
H
Suzuki
Mayumi
M
Minami
Seigo
S
Iwasaki
Takeo
T
Goya
Sho
S
Kijima
Takashi
T
Kumagai
Toru
T
Yoshida
Mitsuhiro
M
Osaki
Tadashi
T
Komori
Toshihisa
T
Mekada
Eisuke
E
Kawase
Ichiro
I
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010447:Peptide Hydrolases / Q000378:metabolism*; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D060225:Tetraspanin 28; D060245:Tetraspanin 29
D015703:Antigens, CD; C554799:Cd81 protein, mouse; C554870:Cd9 protein, mouse; D008562:Membrane Glycoproteins; D060225:Tetraspanin 28; D060245:Tetraspanin 29; D010447:Peptide Hydrolases