CCL20

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Chemokine (C-C motif) ligand 20 (CCL20) or liver activation regulated chemokine (LARC) or Macrophage Inflammatory Protein-3 (MIP3A) is a small cytokine belonging to the CC chemokine family. It is strongly chemotactic for lymphocytes and weakly attracts neutrophils.[1] CCL20 is implicated in the formation and function of mucosal lymphoid tissues via chemoattraction of lymphocytes and dendritic cells towards the epithelial cells surrounding these tissues. CCL20 elicits its effects on its target cells by binding and activating the chemokine receptor CCR6.[2]

Gene expression of CCL20 can be induced by microbial factors such as lipopolysaccharide (LPS), and inflammatory cytokines such as tumor necrosis factor and interferon-γ, and down-regulated by IL-10.[3] CCL20 is expressed in several tissues with highest expression observed in peripheral blood lymphocytes, lymph nodes, liver, appendix, and fetal lung and lower levels in thymus, testis, prostate and gut.[1][4] The gene for CCL20 (scya20) is located on chromosome 2 in humans.[5]

Recent research [6] in an animal model of multiple sclerosis known as experimental autoimmune encephalitis (EAE) demonstrated that regional neural activation can create "gates" for pathogenic CD4+ T cells to enter the CNS by increasing CCL20 expression, especially at L5. Sensory nerve stimulation, elicited by using muscles in the leg or electrical stimulation as in Arima et al., 2012, activates sympathetic neurons whose axons run through the dorsal root ganglia containing cell bodies of the stimulated afferent sensory nerve. Sympathetic neuronal activity activates IL-6 amplifier resulting in increased regional CCL20 expression and subsequent pathogenic CD4+ T cell accumulation at the same spinal cord level. CCL20 expression was observed to be dependent on IL-6 amplifier activation, which is dependent on NF-κB and STAT3 activation. This research provides evidence for a critical role for CCL20 in autoimmune pathogenesis of the central nervous system.

References

  1. 1.0 1.1 Hieshima K, Imai T, Opdenakker G, Van Damme J, Kusuda J, Tei H, Sakaki Y, Takatsuki K, Miura R, Yoshie O, Nomiyama H (1997). "Molecular cloning of a novel human CC chemokine liver and activation-regulated chemokine (LARC) expressed in liver. Chemotactic activity for lymphocytes and gene localization on chromosome 2". J. Biol. Chem. 272 (9): 5846–5853. doi:10.1074/jbc.272.9.5846. PMID 9038201.
  2. Baba M, Imai T, Nishimura M, Kakizaki M, Takagi S, Hieshima K, Nomiyama H, Yoshie O (1997). "Identification of CCR6, the specific receptor for a novel lymphocyte-directed CC chemokine LARC". J. Biol. Chem. 272 (23): 14893–14898. doi:10.1074/jbc.272.23.14893. PMID 9169459.
  3. Schutyser E, Struyf S, Menten P, Lenaerts JP, Conings R, Put W, Wuyts A, Proost P, Van Damme J (2000). "Regulated production and molecular diversity of human liver and activation-regulated chemokine/macrophage inflammatory protein-3 alpha from normal and transformed cells". J. Immunol. 165 (8): 4470–7. doi:10.4049/jimmunol.165.8.4470. PMID 11035086.
  4. Rossi DL, Vicari AP, Franz-Bacon K, McClanahan TK, Zlotnik A (1997). "Identification through bioinformatics of two new macrophage proinflammatory human chemokines: MIP-3alpha and MIP-3beta". J. Immunol. 158 (3): 1033–6. PMID 9013939.
  5. Nelson RT, Boyd J, Gladue RP, Paradis T, Thomas R, Cunningham AC, Lira P, Brissette WH, Hayes L, Hames LM, Neote KS, McColl SR (2001). "Genomic organization of the CC chemokine mip-3alpha/CCL20/larc/exodus/SCYA20, showing gene structure, splice variants, and chromosome localization". Genomics. 73 (1): 28–37. doi:10.1006/geno.2001.6482. PMID 11352563.
  6. Regional Neural Activation Defines a Gateway for Autoreactive T Cells to Cross the Blood-Brain Barrier | author = Arima, Yasunobu; Harada, Masaya; Kamimura, Daisuke; Park, Jin-Haeng; Kawano, Fuminori; Yull, Fiona E.; Kawamoto, Tadafumi; Iwakura, Yoichiro; Betz, Ulrich A.K.; Marquez, Gabriel; Blackwell, Timothy S.; Ohira, Yoshinobu; Hirano, Toshio; Murakami, Masaaki | Cell doi:10.1016/j.cell.2012.01.022 (volume 148 issue 3 pp.447 - 457)

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