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Autotaxin loss accelerates intestinal inflammation by suppressing TLR4‐mediated immune responses
Author(s) -
Kim Su Jin,
Howe Cody,
Mitchell Jonathon,
Choo Jieun,
Powers Alexandra,
Oikonomopoulos Angelos,
Pothoulakis Charalabos,
Hommes Daniel W,
Im Eunok,
Rhee Sang Hoon
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201949332
Subject(s) - library science , pharmacy , medicine , political science , family medicine , computer science
Autotaxin (ATX) converts lysophosphatidylcholine and sphingosyl‐phosphorylcholine into lysophosphatidic acid and sphingosine 1‐phosphate, respectively. Despite the pivotal function of ATX in lipid metabolism, mechanisms by which ATX regulates immune and inflammatory disorders remain elusive. Here, using myeloid cell lineage‐restricted Atx knockout mice, we show that Atx deficiency disrupts membrane microdomains and lipid rafts, resulting in the inhibition of Toll‐like receptor 4 (TLR4) complex formation and the suppression of adaptor recruitment, thereby inhibiting TLR4‐mediated responses in macrophages. Accordingly, TLR4‐induced innate immune functions, including phagocytosis and iNOS expression, are attenuated in Atx‐deficient macrophages. Consequently, Atx −/− mice exhibit a higher bacterial prevalence in the intestinal mucosa compared to controls. When combined with global Il10 −/− mice, which show spontaneous colitis due to the translocation of luminal commensal microbes into the mucosa, myeloid cell lineage‐restricted Atx knockout accelerates colitis development compared to control littermates. Collectively, our data reveal that Atx deficiency compromises innate immune responses, thereby promoting microbe‐associated gut inflammation.