TY - JOUR
T1 - ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice
AU - Suzuki, Shoji
AU - Ishii, Makoto
AU - Asakura, Takanori
AU - Namkoong, Ho
AU - Okamori, Satoshi
AU - Yagi, Kazuma
AU - Kamata, Hirofumi
AU - Kusumoto, Tatsuya
AU - Kagawa, Shizuko
AU - Hegab, Ahmed E.
AU - Yoda, Masaki
AU - Horiuchi, Keisuke
AU - Hasegawa, Naoki
AU - Betsuyaku, Tomoko
N1 - Funding Information:
The authors thank Miyuki Yamamoto, Sachika Wada, and Dr. Haiyue Zhang for research assistance and Akira Sonoda (Keio-Med Open Access Facility, Keio University School of Medicine) for skilled technical assistance. Some of the results of these studies have been previously reported in the form of abstracts (36, 37). This work was supported by a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (to S.S.), a Grant-in-Aid for Scientific Research (B) (18H02821) (to M.I.), and a Grant-in-Aid for Challenging Exploratory Research (18K19566) (to M.I.).
Funding Information:
This work was supported by a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (to S.S.), a Grant-in-Aid for Scientific Research (B) (18H02821) (to M.I.), and a Grant-in-Aid for Challenging Exploratory Research (18K19566) (to M.I.).
Publisher Copyright:
© 2020 the American Physiological Society
PY - 2020/6
Y1 - 2020/6
N2 - Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre(Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.
AB - Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre(Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.
KW - A disintegrin and metalloproteinase 17
KW - CD62L
KW - Chronic obstructive pulmonary disease
KW - Emphysema
KW - Tumor necrosis factor-α-converting enzyme
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U2 - 10.1152/ajplung.00214.2019
DO - 10.1152/ajplung.00214.2019
M3 - Article
C2 - 32130031
AN - SCOPUS:85084935087
SN - 1040-0605
VL - 318
SP - L1172-L1182
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 6
ER -