Involvement of the lysophosphatidic acid-generating enzyme autotaxin in lymphocyte-endothelial cell interactions

Tae Nakasaki, Toshiyuki Tanaka, Shinichi Okudaira, Michi Hirosawa, Eiji Umemoto, Kazuhiro Otani, Soojung Jin, Zhongbin Bai, Haruko Hayasaka, Yoshinori Fukui, Katsuyuki Aozasa, Naoya Fujita, Takashi Tsuruo, Keiichi Ozono, Junken Aoki, Masayuki Miyasaka

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Abstract

Autotaxin (ATX) is a secreted protein with lysophospholipase D activity that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine. Here we report that functional ATX is selectively expressed in high endothelial venules (HEVs) of both lymph nodes and Peyer's patches. ATX expression was developmentally regulated and coincided with lymphocyte recruitment to the lymph nodes. In adults, ATX expression was independent of HEV-expressed chemokines such as CCL21 and CXCL13, innate immunity signals including those via TLR4 or MyD88, and of the extent of lymphocyte trafficking across the HEVs. ATX expression was induced in venules at sites of chronic inflammation. Receptors for the ATX enzyme product LPA were constitutively expressed in HEV endothelial cells (ECs). In vitro, LPA induced strong morphological changes in HEV ECs. Forced ATX expression caused cultured ECs to respond to lysophosphatidylcholine, up-regulating lymphocyte binding to the ECs in a LPA receptor-dependent manner under both static and flow conditions. Although in vivo depletion of circulating ATX did not affect lymphocyte trafficking into the lymph nodes, we surmise, based on the above data, that ATX expressed by HEVs acts on HEVs in situ to facilitate lymphocyte binding to ECs and that ATX in the general circulation does not play a major role in this process. Tissue-specific inactivation of ATX will verify this hypothesis in future studies of its mechanism of action.

Original languageEnglish
Pages (from-to)1566-1576
Number of pages11
JournalAmerican Journal of Pathology
Volume173
Issue number5
DOIs
Publication statusPublished - Nov 2008

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All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Nakasaki, T., Tanaka, T., Okudaira, S., Hirosawa, M., Umemoto, E., Otani, K., ... Miyasaka, M. (2008). Involvement of the lysophosphatidic acid-generating enzyme autotaxin in lymphocyte-endothelial cell interactions. American Journal of Pathology, 173(5), 1566-1576. https://doi.org/10.2353/ajpath.2008.071153