Autotaxin Downregulates LPS‐Induced Microglia Activation and Pro‐Inflammatory Cytokines Production

Abstract

Inflammation is essential in defense against infection or injury. It is tightly regulated, as over-response can be detrimental, especially in immune-privileged organs such as the central nervous system (CNS). Microglia constitutes the major source of inflammatory factors, but are also involved in the regulation of the inflammation and in the reparation. Autotaxin (ATX), a phospholipase D, converts lysophosphatidylcholine into lysophosphatidic acid (LPA) and is upregulated in several CNS injuries. LPA, a pleiotropic immunomodulatory factor, can induce multiple cellular processes including morphological changes, proliferation, death and survival. We investigated ATX effects on microglia inflammatory response to lipopolysaccharide (LPS), mimicking gram-negative infection. Murine BV-2 microglia and stable transfected, overexpressing ATX-BV-2 (A+) microglia were treated with LPS. Tumor necrosis factor α (TNFα), interleukin (IL)-6 and IL-10 mRNA and proteins levels were examined by qRT-PCR and ELISA, respectively. Secreted LPA was quantified by a radioenzymatic assay and microglial activation markers (CD11b, CD14, B7.1 and B7.2) were determined by flow cytometry. ATX expression and LPA production were significantly enhanced in LPS treated BV-2 cells. LPS induction of mRNA and protein level for TNFα and IL-6 were inhibited in A+ cells, while IL-10 was increased. CD11b, CD14, and B7.1 and B7.2 expressions were reduced in A+ cells. Our results strongly suggest deactivation of microglia and an IL-10 inhibitory of ATX with LPS induced microglia activation.

Lysophosphatidic acid up-regulates IL-10 production to inhibit TNF-α synthesis in Mϕs stimulated with LPS

“…An inhibitory activity of IL‐10 toward LPS‐induced production of TNF‐α was described earlier, but a role of IL‐10 in the immunomodulatory activity of LPA has not been addressed to date. Only Awada and coworkers observed an increased level of IL‐10 in microglia overexpressing autotaxin, an enzyme producing LPA . Recently, it was shown that IL‐10 applied after LPS inhibited Tnfa expression but did not influence Ccl5/Rantes expression and INF‐β secretion, and our data are in agreement with those results.…”

“…Both LPS and LPA are well‐known signaling molecules and their respective signaling pathways can intersect in specific pathophysiological conditions, e.g., in atherosclerotic lesions . Several earlier reports have suggested that LPA can have both pro‐ and anti‐inflammatory activity depending on cell type and physiological context . In our studies, we did not observe any production of pro‐inflammatory cytokines in pMϕ or J774 cells treated with LPA only.…”

“…In accordance, mice deficient in LPA 2 , one of LPA receptors, exhibited stronger lung inflammatory response to LPS than did the wild type counterparts . LPA also attenuated the LPS‐dependent production of several cytokines (TNF‐α, IL‐6, CCL2/MCP‐1), expression of cyclooxygenase‐2 and inducible NO synthase in murine Mϕs, bone marrow‐derived dendritic cells and murine BV‐2 microglia . On the other hand, it has been shown that another LPA receptor, LPA 1 , apparently exhibits pro‐inflammatory activity, as its inhibition or knockdown blunted the LPS‐induced inflammation in mouse lung and peritoneum .…”

Role of the Autotaxin-LPA Pathway in Dexamethasone-Induced Fibrotic Responses and Extracellular Matrix Production in Human Trabecular Meshwork Cells

“…This might be because ATX can regulate several cytokines and evoke signals other than those of the Rho/ROCK pathway. [60][61][62] In addition, increased levels of LPA have been shown to induce profibrotic TGF-b signaling via G protein-coupled receptor (GPCR) signaling. 63,64 Therefore, in future studies investigating the role of the ATX-LPA pathway in the regulation of AH outflow and IOP, we plan to undertake a detailed assessment of the balance and interactions between the TGF-b2 and ATX-LPA pathways as well as their involvement in ocular hypertension and etiology of glaucoma.…”

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

“…This protects microglia cells against damage from H 2 O 2 , an effect which is partially reversed in the presence of the mixed LPA 1/3 antagonist Ki16425 [46] . A follow-up study showed that ATX overexpression in microglia limited the pro-inflammatory response to lipopolysaccharide exposure, mimicking Gram-negative infection [47] . ATX is expressed in high endothelial venules (HEVs) in lymph nodes and other secondary lymphoid tissues [48] and mediates lymphocyte extravasation, which is crucial for maintaining immune homeostasis [49][50][51] .…”