title: CCR2 Expression in Neutrophils Plays a Critical Role in Their Migration Into the Joints in Rheumatoid Arthritis.
abstract: OBJECTIVE
  Infiltration of neutrophils into the joints plays an important role in bone erosion and articular destruction in rheumatoid arthritis (RA). Neutrophil trafficking during inflammation is a process that involves activation of chemotactic receptors. Recent findings suggest that changes in chemotactic receptor patterns could occur in neutrophils under certain inflammatory conditions. The aim of this study was to evaluate the gain of responsiveness of neutrophils to CCL2 in RA patients and to assess the role of CCL2 in driving neutrophil infiltration into the joints.
  
  
  METHODS
  Neutrophils were purified from the peripheral blood of patients with RA or from mice with antigen-induced arthritis (AIA). Expression of CCR2 was evaluated using polymerase chain reaction, flow cytometry, and immunofluorescence analyses. In vitro chemotaxis to CCL2 was assayed to evaluate the functional significance of de novo CCR2 expression. The murine AIA model was used to evaluate the in vivo role of CCR2 in neutrophil infiltration into the joints.
  
  
  RESULTS
  High CCR2 expression and responsiveness to CCL2 were observed in neutrophils from the blood of patients with early RA and in neutrophils from the blood and bone marrow of mice with AIA. Genetic deficiency or pharmacologic inhibition of CCR2 protected against the infiltration of neutrophils into the joints. This protection was not associated with an impairment of the neutrophil chemotactic ability or CXC chemokine production in the joints. Moreover, adoptive transfer of wild-type mouse neutrophils to CCR2-deficient mice restored neutrophil infiltration and the articular mechanical hyperalgesia associated with joint inflammation.
  
  
  CONCLUSIONS
  These findings suggest that CCR2 is directly involved in the detrimental infiltration of neutrophils into the joints in patients with RA, showing a new inflammatory role of CCR2 during RA flares or active disease.
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Jhimmy
authors.initials: J
authors.lastname: Talbot
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Francine J
authors.initials: FJ
authors.lastname: Bianchini
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Danilele C
authors.initials: DC
authors.lastname: Nascimento
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Rene D R
authors.initials: RD
authors.lastname: Oliveira
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Fabricio O
authors.initials: FO
authors.lastname: Souto
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Larissa G
authors.initials: LG
authors.lastname: Pinto
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Raphael S
authors.initials: RS
authors.lastname: Peres
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Jaqueline R
authors.initials: JR
authors.lastname: Silva
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Sergio C L
authors.initials: SC
authors.lastname: Almeida
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Paulo
authors.initials: P
authors.lastname: Louzada-Junior
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: University of São Paulo, Ribeirão Preto Medical School, Ribeirao Preto, Sao Paulo, Brazil.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Alves-Filho
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D018932:Chemokine CCL2 / Q000494:pharmacology; D002633:Chemotaxis / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007596:Joints / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2