title: CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice.
abstract: OBJECTIVE
  Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein- and L-arginine-induced acute pancreatitis in mice.
  
  
  METHODS
  Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages.
  
  
  RESULTS
  Almost all types of immune cells, except for CD11b(high)CD11c(-) cells, were detected in the pancreas of healthy mice. However, activated CD11b(high)CD11c(-) cells, including Gr-1(low) macrophages and Gr-1(high) cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2(-/-) mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11b(high)CD11c(-)Gr-1(low) macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11b(high)CD11c(-)Gr-1(low) macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1(low) macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b(high)CD11c(-)Gr-1(low) macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2.
  
  
  CONCLUSIONS
  Cerulein induction of pancreatitis in mice involves migration of CD11b(high)CD11c(-)Gr-1(low) macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3-dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis.
authors.affiliation: Department of Gastroenterology and Hepatology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Saeki
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Masaru
authors.initials: M
authors.lastname: Nakano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Naoteru
authors.initials: N
authors.lastname: Miyata
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Sujino
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Takaishi
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Ono
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Shigenari
authors.initials: S
authors.lastname: Hozawa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000208:Acute Disease; D000818:Animals; D001120:Arginine; D015415:Biomarkers / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002108:Ceruletide; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002633:Chemotaxis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004798:Enzymes / Q000097:blood; D007113:Immunity, Innate; D008212:Lymphocyte Depletion; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010227:Parabiosis; D054390:Receptors, CCR2 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D039481:CD11b Antigen; D039521:CD11c Antigen; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D004798:Enzymes; C503133:Gr-1 protein, mouse; C499308:Rag2 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D002108:Ceruletide; D001120:Arginine