Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis

Zhongbin Bai, Linjun Cai, Eiji Umemoto, Akira Takeda, Kazuo Tohya, Yutaka Komai, Punniyakoti Thanikachalam Veeraveedu, Erina Hata, Yuki Sugiura, Akiko Kubo, Makoto Suematsu, Haruko Hayasaka, Shinichi Okudaira, Junken Aoki, Toshiyuki Tanaka, Harald M.H.G. Albers, Huib Ovaa, Masayuki Miyasaka

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2036-2048
Number of pages13
JournalJournal of Immunology
Volume190
Issue number5
DOIs
Publication statusPublished - 2013 Mar 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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