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    • Despite the growing knowledge surrounding the link between A

    2023-04-10

    Despite the growing knowledge surrounding the link between ATX and cholestatic pruritus in PBC, it remains unclear if the role of the ATX-LPA signaling axis includes lymphocytes homing in the liver of PBC, and if the resulting inflammation is associated with PBC pruritus (Fig. 3). PBC is characterized by chronic, nonsuppurative cholangitis with an inflammatory infiltrate consisting of lymphocytes and mononuclear irak inhibitor in close contact with the basal membrane of biliary epithelial cells undergoing necrosis, and a cellular infiltrate of plasma cells, macrophages, and polymorphonuclear cells [59]. The clinical development of ATX inhibitors [69] may allow the role of the ATX-LPA axis in PBC-associated pruritus to be defined. Clearly there are major unmet needs in pruritus in PBC. Indeed, despite all the murine models and the intensive work on the immunobiology of patients with PBC, there are still major gaps in improving therapy for all aspects of this disease.
    Take-home messages
    Introduction For many years, it was thought that the central nervous system (CNS) was an “immune privileged” organ neither susceptible nor contributing to inflammation. Nowadays, it has been shown that the CNS exhibits characteristics of inflammation, and in response to injury, infectious agents and resident CNS cells, generate inflammatory mediators (Hauser and Oksenberg, 2006). Multiple sclerosis (MS) is characterized by the presence of inflammatory demyelinating lesions in the CNS and inflammatory reactions play a crucial role in the pathogenesis of the disease (Bitsch et al., 2000). The inflammatory process is further associated with up-regulated expression of adhesion molecules, chemokines and cytokines not only in the inflammatory infiltrates but also in part in astrocytes (Lucchinetti et al., 1996). The disease, in approximately 85% of patients with newly diagnosed definite MS, starts with a relapsing remitting phase (RRMS), which later (normally after decades) converts into a secondary progressive phase (SPMS) for the majority. In primary progressive MS patients (PPMS) a relapsing stage is not present and the disease starts with continuous progression from onset (Bitsch and Brück, 2002). Inflammation is a devastating process in all types of MS especially when the disease is in an active stage. However, inflammation is more pronounced in relapsing–remitting MS with respect to other types of the disease (Frischer et al., 2009). One of the key enzymes that promotes inflammation is autotaxin (ATX), converting lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) (Tokumura et al., 2002). Although, LPA can be produced by other enzymatic reactions, a large body of research indicates that the main source of LPA synthesis is ATX activity (Stracke et al., 1992). LPA is a lipid mediator with multiple biological actions, acting through cell surface G protein-coupled receptors to elicit a wide range of cellular responses such as cell proliferation and cytokine production (van Meeteren and Moolenaar, 2007). LPA is also capable of protecting T cells from apoptosis through the suppression of Bax (Goetzl et al., 1999). On the other hand, ATX is able to hydrolyze sphingosylphosphorylcholine (SPC) to sphingosine-1-phosphate (S1P), a bioactive lipid mediator, sending out signals through a family of G-protein-coupled receptors to control cellular differentiation and survival, as well as the vital functions of several types of immune cell (Hla, 2003). S1P is one of the best targets for therapy in MS. The biological action of S1P is inhibited by FTY-720 (fingolimod) which attenuates trafficking of harmful T cells entering the brain by regulating sphingosine-1-phosphate receptors (S1PRs) (Massberg and von Andrian, 2006). Several lines of evidence show that ATX may be involved in the pathogenesis of some autoimmune diseases. A study performed by Nikitopoulou et al. (2012) demonstrated that ATX expression in synovial fibroblasts is required for the pathogenesis of rheumatoid arthritis (RA). They showed that ATX is increased in synovial fibroblasts of patients afflicted with RA in comparison with healthy individuals. In 2004, Hammack et al. (2004) did an interesting experiment deducing that there were four proteins exclusively expressed in cerebrospinal fluid (CSF) of MS patients including CRTAC-1B (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signaling glycoprotein), and autotaxin while these proteins were not detectable in CSF of patients with other neurological diseases (OND). Based on the aforementioned statements and involvement of ATX in inflammatory diseases, we decided to measure the activity of ATX in the CSF of MS patients in order to see whether ATX activity is increased in MS or not.