Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis.
Lymphocyte extravasation from the high endothelial venules (HEVs) of lymph nodes is crucial for the maintenance of immune homeostasis, but its molecular mechanism remains largely unknown. In this article, we report that lymphocyte transmigration across the basal lamina of the HEVs is regulated, at least in part, by autotaxin (ATX) and its end-product, lysophosphatidic acid (LPA). ATX is an HEV-associated ectoenzyme that produces LPA from lysophosphatidylcholine (LPC), which is abundant in the systemic circulation. In agreement with selective expression of ATX in HEVs, LPA was constitutively and specifically detected on HEVs. In vivo, inhibition of ATX impaired the lymphocyte extravasation from HEVs, inducing lymphocyte accumulation within the endothelial cells (ECs) and sub-EC compartment; this impairment was abrogated by LPA. In vitro, both LPA and LPC induced a marked increase in the motility of HEV ECs; LPC's effect was abrogated by ATX inhibition, whereas LPA's effect was abrogated by ATX/LPA receptor inhibition. In an in vitro transmigration assay, ATX inhibition impaired the release of lymphocytes that had migrated underneath HEV ECs, and these defects were abrogated by LPA. This effect of LPA was dependent on myosin II activity in the HEV ECs. Collectively, these results strongly suggest that HEV-associated ATX generates LPA locally; LPA, in turn, acts on HEV ECs to increase their motility, promoting dynamic lymphocyte-HEV interactions and subsequent lymphocyte transmigration across the basal lamina of HEVs at steady state.
Laboratory of Immunodynamics, World Premier International Research Center Initiative-Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.
Zhongbin
Z
Bai
Linjun
L
Cai
Eiji
E
Umemoto
Akira
A
Takeda
Kazuo
K
Tohya
Yutaka
Y
Komai
Punniyakoti Thanikachalam
PT
Veeraveedu
Erina
E
Hata
Yuki
Y
Sugiura
Akiko
A
Kubo
Makoto
M
Suematsu
Haruko
H
Hayasaka
Shinichi
S
Okudaira
Junken
J
Aoki
Toshiyuki
T
Tanaka
Harald M H G
HM
Albers
Huib
H
Ovaa
Masayuki
M
Miyasaka
D000818:Animals; D001485:Basement Membrane / Q000187:drug effects* / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism / Q000494:pharmacology*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D024462:Myosin Type II / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014699:Venules / Q000187:drug effects* / Q000378:metabolism; D000099189:Lysophospholipase D
D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D024462:Myosin Type II; D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid