title: Chemokine-chemokine receptor CCL2-CCR2 and CX3CL1-CX3CR1 axis may play a role in the aggravated inflammation in primary biliary cirrhosis.
abstract: OBJECTIVE
  Senescent cells can alter local tissue environments by secretion of various senescence-associated secretory phenotypes (SASP), such as cytokines and chemokines. Given senescent biliary epithelial cells (BECs) in damaged small bile ducts in primary biliary cirrhosis (PBC) show increased expression of chemokines CCL2 and CX3CL1 as SASP, we further examined an involvement of CCL2/CCR2 and CX3CL1/CX3CR1 systems in the pathogenesis of PBC.
  
  
  METHODS
  We examined immunohistochemically the expression of CCR2, CX3CR1, CCL2 and CX3CL1 in livers taken from the patients with PBC (n = 45) and control livers (n = 78), such as chronic viral hepatitis (CVH; n = 39). CCR2 or CX3CR1-expressing cells were characterized by double immunofluorescence with CD3, CD4, CD8, CD56 or CD68.
  
  
  RESULTS
  CCR2 is expressed in round cells, epithelioid cells and dendritic cells and most CCR2-positive cells were CD68-positive. Infiltration of CCR2-positive cells in the intraepithelial layer or around small bile ducts was significantly more extensive in PBC than CVH and normal liver (p < 0.05) and was significantly correlated with the expression of CCL2 in BECs (p < 0.01). Most CX3CR1-expressing inflammatory cells were CD3-positive T cells (CD8 > CD4). Infiltration of CX3CR1-positive cells in the intraepithelial layer and around small bile ducts was significantly more extensive in PBC than control livers (p < 0.05) and was significantly correlated with the expression of CX3CL1 in BECs (p < 0.05).
  
  
  CONCLUSIONS
  CCL2 and CX3CL1 produced by senescent BECs may promote infiltration of corresponding CCR2 and CX3CR1-expressing cells and further aggravate inflammation in bile duct lesion in PBC.
authors.affiliation: Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Sasaki
authors.forename: Masami
authors.initials: M
authors.lastname: Miyakoshi
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Yasuni
authors.initials: Y
authors.lastname: Nakanuma
mesh_terms: D001652:Bile Ducts / Q000276:immunology* / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D016022:Case-Control Studies; D016922:Cellular Senescence; D018932:Chemokine CCL2 / Q000032:analysis*; D054428:Chemokine CX3CL1 / Q000032:analysis*; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000473:pathology; D054390:Receptors, CCR2 / Q000032:analysis*; D019707:Receptors, Chemokine / Q000032:analysis*
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D018836:Inflammation Mediators; D054390:Receptors, CCR2; D019707:Receptors, Chemokine