TY - JOUR
T1 - Abl family tyrosine kinases govern IgG extravasation in the skin in a murine pemphigus model
AU - Ono, Sachiko
AU - Egawa, Gyohei
AU - Nomura, Takashi
AU - Kitoh, Akihiko
AU - Dainichi, Teruki
AU - Otsuka, Atsushi
AU - Nakajima, Saeko
AU - Amagai, Masayuki
AU - Matsumoto, Fumi
AU - Yamamoto, Mami
AU - Kubota, Yoshiaki
AU - Takai, Toshiyuki
AU - Honda, Tetsuya
AU - Kabashima, Kenji
N1 - Funding Information:
This work was supported by the Japan Society for the Promotion of Science KAKENHI (201740146), Grants-in-Aid for Scientific Research 15H05790, 15H1155, 15K15417, Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO) (16021031300), and Japan Agency for Medical Research and Development (AMED) (16ek0410011h0003, 16he0902003h0002, 18ak0101057h0003). We thank Dr Y. Hamasaki (Kyoto University). We thank H. Doi, K. Tomari, N. Ishizawa, and M. Hiraiwa (Kyoto University), and K. Okamoto-Furuta and H. Kohda of Electron Microscopic Study, Center for Anatomical studies, Graduate School of Medicine (Kyoto University) for their technical assistance. We thank Z. Chow for language editing.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders.
AB - The pathway of homeostatic IgG extravasation is not fully understood, in spite of its importance for the maintenance of host immunity, the management of autoantibody-mediated disorders, and the use of antibody-based biologics. Here we show in a murine model of pemphigus, a prototypic cutaneous autoantibody-mediated disorder, that blood-circulating IgG extravasates into the skin in a time- and dose-dependent manner under homeostatic conditions. This IgG extravasation is unaffected by depletion of Fcγ receptors, but is largely attenuated by specific ablation of dynamin-dependent endocytic vesicle formation in blood endothelial cells (BECs). Among dynamin-dependent endocytic vesicles, IgG co-localizes well with caveolae in cultured BECs. An Abl family tyrosine kinase inhibitor imatinib, which reduces caveolae-mediated endocytosis, impairs IgG extravasation in the skin and attenuates the murine pemphigus manifestations. Our study highlights the kinetics of IgG extravasation in vivo, which might be a clue to understand the pathological mechanism of autoantibody-mediated autoimmune disorders.
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U2 - 10.1038/s41467-019-12232-3
DO - 10.1038/s41467-019-12232-3
M3 - Article
C2 - 31570755
AN - SCOPUS:85072763361
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4432
ER -