Essential role of CCR2 in neutrophil tissue infiltration and multiple organ dysfunction in sepsis.
BACKGROUND
Sepsis is defined as a systemic inflammatory response to infection, which in its severe form is associated with multiple organ dysfunction syndrome (MODS). The precise mechanisms by which MODS develops remain unclear. Neutrophils have a pivotal role in the defense against infections; however, overwhelming activation of neutrophils is known to elicit tissue damage.


OBJECTIVE
We investigated the role of the chemokine receptor CCR2 in driving neutrophil infiltration and eliciting tissue damage in remote organs during sepsis.


METHODS
Sepsis was induced in wild-type mice treated with CCR2 antagonist (RS504393) or CCR2(-/-) mice by cecal ligation and puncture (CLP) model. Neutrophil infiltration into the organs was measured by myeloperoxidase activity and fluorescence-activated cell sorter. CCR2 expression and chemotaxis were determined in neutrophils stimulated with Toll-like receptor agonists or isolated from septic mice and patients.


RESULTS
CCR2 expression and responsiveness to its ligands was induced in circulating neutrophils during CLP-induced sepsis by a mechanism dependent on Toll-like receptor/nuclear factor-κB pathway. Genetic or pharmacologic inhibition of CCR2 protected mice from CLP-induced mortality. This protection was associated with lower infiltration of neutrophils into the lungs, heart, and kidneys and reduced serum biochemical indicators of organ injury and dysfunction. Importantly, neutrophils from septic patients express high levels of CCR2, and the severity of patient illness correlated positively with increasing neutrophil chemotaxis to CCR2 ligands.


CONCLUSIONS
Collectively, these data identify CCR2 as a key receptor that drives the inappropriate infiltration of neutrophils into remote organs during sepsis. Therefore, CCR2 blockade is a novel potential therapeutic target for treatment of sepsis-induced MODS.
Souto
Fabricio O
FO
Department of Pharmacology, School of Medicine Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
Alves-Filho
José C
JC
Turato
Walter M
WM
Auxiliadora-Martins
Maria
M
Basile-Filho
Aníbal
A
Cunha
Fernando Q
FQ
D000818:Animals; D015415:Biomarkers / Q000097:blood; D002633:Chemotaxis; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000097:blood* / Q000209:etiology; D009504:Neutrophils / Q000378:metabolism*; D009195:Peroxidase / Q000097:blood; D054390:Receptors, CCR2 / Q000097:blood*; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000097:blood* / Q000150:complications; D015854:Up-Regulation
D015415:Biomarkers; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D009195:Peroxidase