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  • calcium ionophore br CXCR CXCR is a homeostatic

    2019-09-11


    CXCR5 CXCR5 is a homeostatic chemokine receptor for lymphocytes and plays a critical role in the development of lymphoid organs as well as regulating the interaction between antigen presenting cells and lymphocytes (Cannons et al., 2012). It is one of the major chemokine receptors dictating normal circulation of lymphocytes in blood and tissues. It is the sole receptor for CXCL13 which is constitutively secreted by stromal cells (Legler et al., 1998). CXCR5 is highly calcium ionophore expressed in B cells, T cells and dendritic cells (Cannons et al., 2012, Leon et al., 2012). CXCR5 is induced in antigen-activated T cells and dendritic cells and together with IL-10 and IL-21, regulates Th2 responses and antibody production by promoting naïve calcium ionophore to differentiate into antibody-producing plasma cells (Morita et al., 2011). The first fish CXCR5 genes were reported in grass carp (C. idella) and fugu (T. rubripes) in 2010 (Xu et al., 2010). The teleost fish CXCR5 gene consists of 2 exons and a single intron. Unlike many other chemokine and chemokine receptor genes which have expanded in teleosts (Bao et al., 2006, Chen et al., 2013, DeVries et al., 2006, Nomiyama et al., 2008, Nomiyama et al., 2011, Xu et al., 2014a), only a single copy of CXCR5 and CXCL13 have been reported. This is also true for cartilaginous fish where a single CXCR5 orthologous gene has been found (Venkatesh et al., 2014). Interestingly, the appearance of CXCR5 coincides with the emergence of the RAG-mediated adaptive immune system consisting of T and B lymphocytes as well as other physiological changes (Fig. 4) (Flajnik and Du Pasquier, 2004, Venkatesh et al., 2014). Jawless fish do not have a classical adaptive immune system but possess B lymphocyte like cells that effect a form of adaptive immunity meditated via receptors containing multiple leucine-rich repeats (Cooper and Herrin, 2010). Extensive in silico analysis also failed to identify any apparent orthologues of CXCR5 in the invertebrate genome databases (unpublished data). There is a paucity of reports on CXCR5 function in fish. In terms of expression, CXCR5 is highly expressed in lymphoid tissues such as kidney and spleen in grass carp and can be modulated by a range of immune stimulants including peptidoglycan, LPS, polyI:C and phytohaemagglutinin (Xu et al., 2010). In zebrafish, CXCR5 is detected in glial cells when they differentiate into neurons in the adult zebrafish brain. It regulates the regenerative neurogenesis response and promotes ventricular cell proliferation when injury occurs in the telencephalon (Kizil et al., 2012). Overexpression of dominant negative CXCR5 variants significantly reduces the number of newborn neurons in lesioned telencephalon in the zebrafish brain (Kizil et al., 2012). These findings demonstrate that CXCR5’s roles in neuron development in the brain and migration of neural cells is likely to be conserved in fish.
    CXCR6 CXCR6, originally referred to as BONZO, is the sole receptor interacting with CXCL16, which is an unusual CXC chemokine in being produced as both membrane bound and soluble forms (Matloubian et al., 2000, Wilbanks et al., 2001). The membrane bound CXCL16 consists of an N-terminal chemokine domain, a highly glycosylated mucin-like stalk, a transmembrane domain, and a short cytoplasmic tail (Matloubian et al., 2000), and functions as a scavenger receptor for oxidised low-density lipoprotein and bacteria as well as an adhesion mediator for leucocytes (Nakayama et al., 2003, Shimaoka et al., 2000, Shimaoka et al., 2004). The soluble form of CXCL16 is generated by proteolytic cleavage of the membrane molecule, involving disintegrin and metalloproteinases (Abel et al., 2004) and coordinates migration of CXCR6+ cells (Borst et al., 2012). CXCL16 is produced by macrophages, dendritic cells, Th1 cells, platelets and cancer cells (Borst et al., 2012, Darash-Yahana et al., 2009, Galkina et al., 2007, Kim et al., 2001, Zernecke et al., 2008). Its expression can be up-regulated by IFN-γ and TNF-α (Abel et al., 2004) and a high level of expression is usually associated with the progression of human diseases such as rheumatoid arthritis (Nanki et al., 2005), atherosclerosis (Galkina et al., 2007), coronary artery disease (Abel et al., 2004), and liver injury (Xu et al., 2005). CXCL16 promotes growth of CXCR6-expressing cancer cells and primary CD4+ T cells in inflammation-associated cancers (Darash-Yahana et al., 2009). Curiously, CXCL16 shares some degree of structural similarities with CX3CL1 (fractalkine) (Wang et al., 2008a).