Essential Role of CCR2 in Neutrophil Tissue Infiltration and Multiple Organ Dysfunction in Sepsis

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, overwh...

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Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2011-01, Vol.183 (2), p.234-242
Main Authors: SOUTO, Fabricio O, ALVES, José C, TURATO, Walter M, AUXILIADORA-MARTINS, Maria, BASILE, Anibal, CUNHA, Fernando Q
Format: Article
Language:English
Subjects:
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Biological and medical sciences
Biomarkers - blood
Chemokines
Chemotaxis
Disease Models, Animal
Emergency and intensive care: infection, septic shock
Enzyme-Linked Immunosorbent Assay - methods
Flow Cytometry - methods
Humans
Infections
Intensive care medicine
Ligands
Medical sciences
Mice
Mice, Inbred C57BL
Multiple organ dysfunction syndrome
Multiple Organ Failure - blood
Multiple Organ Failure - etiology
Neutrophils
Neutrophils - metabolism
Peroxidase - blood
Receptors, CCR2 - blood
Sepsis
Severity of Illness Index
Shock, Septic - blood
Shock, Septic - complications
Up-Regulation
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Summary: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. We investigated the role of the chemokine receptor CCR2 in driving neutrophil infiltration and eliciting tissue damage in remote organs during sepsis. 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. 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201003-0416oc