MCP-1 protects mice in lethal endotoxemia.

Zisman, David A.; Kunkel, Steven L.; Strieter, Robert M.; Tsai, Wan C.; Bucknell, Kathy A.; Wilkowski, Jodi M.; Standiford, Theodore J.

doi:10.1172/jci119475

Cited by 234 publications

(192 citation statements)

References 27 publications

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“…It was therefore important to note that CCR2 blockade markedly elevated both local and systemic IL-10 levels during septic peritonitis. These findings are consistent with previous work showing that neutralization of CCL2 augmented IL-10 concentrations in serum of LPS-treated mice and in kidneys of mice subjected to cecal ligation and puncture [18,40]. Down-regulation of IL-10 may therefore represent an important function of the CCR2 pathway in sepsis.…”

Section: Discussionsupporting

confidence: 92%

“…We also demonstrate that these effects were mediated by both MyD88-dependent and -independent mechanisms. Considered together with previous work showing that neutralization of the CCR2 ligand CCL2 had detrimental effects in murine endotoxemia and in a model of acute septic peritonitis [18,19], these studies provide strong evidence for an important protective role of CCR2 engagement in sepsis. Analysis of peritoneal chemokine levels of septic mice suggested that production of the CCR2 ligands CCL2 and CCL12 was largely independent of the common TLR signaling adapter protein MyD88.…”

Section: Discussionsupporting

confidence: 55%

“…CCL2 and CCL12, which are ligands for the chemokine receptor CCR2, are released at high levels during human and experimental sepsis [18][19][20][21][22]. Moreover, previous investigations in a murine model of acute septic peritonitis showed CCL2 production in liver and lung to occur in a MyD88-independent fashion [11].…”

Section: Discussionmentioning

confidence: 99%

“…Elevated levels of CCL2 have been detected in plasma of sepsis patients, after administration of LPS to human volunteers, and in animal models of endotoxemia or septic peritonitis [11,[18][19][20][21][22]. Moreover, neutralization of CCL2 aggravated the lethal effects of LPS administration or cecal ligation and puncture in experimental animals [18,19]. CCL2 exerts its biological effects by binding to the chemokine receptor CCR2 that also serves as a receptor for the other CCL2 subfamily members [23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

Feterowski

Mack²,

Weighardt

et al. 2004

Eur J Immunol

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Chemokine receptors are important for recruiting leukocytes to sites of infection and may contribute to immune cell activation. The present study investigated the role of the chemokine receptor CCR2 in polymicrobial septic peritonitis. The results showed that peritoneal production of the CCR2 ligands CCL2 and CCL12 in septic mice was largely independent of the common Toll-like receptor signaling adaptor MyD88. Antibody blockade of CCR2 reduced the recruitment of macrophages and neutrophils to the infected peritoneal cavities of both wild-type and MyD88-deficient mice, suggesting that CCR2 engagement contributes to the MyD88-independent cellular response against polymicrobial septic peritonitis. Notably, administration of blocking CCR2 antibodies markedly increased local and systemic IL-10 levels in septic wild-type mice, whereas IL-10 was not detected in MyD88-deficient mice irrespective of whether CCR2 was blocked or not. Inhibition of CCR2 directly augmented Tolllike receptor-induced IL-10, but not TNF and IL-6, production of macrophages in vitro. Concomitant with enhanced IL-10 production, CCR2 blockade caused impaired bacterial clearance and aggravated kidney injury in wild-type, but not MyD88-null mice. These results indicate that CCR2 engagement modulates the innate immune response to polymicrobial septic peritonitis by both MyD88-dependent and -independent processes and suggest that a major function of CCR2 in sepsis is to attenuate IL-10 production and IL-10-mediated suppression of host defense.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

Feterowski

Mack²,

Weighardt

et al. 2004

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…The level of sensitivity of LPS-pretreated mice to L. monocytogenes was similar to that seen in transgenic mice expressing high levels of circulating MCP-1 [22], which might be partially due to receptor (CCR2) desensitization on blood monocytes by the high levels of MCP-1. It has been shown that in mice as well as in humans and baboons, LPS induced a rapid and substantial increase in MCP-1 levels [23][24][25]. The increased level of MCP-1 in LPS-treated mice could cause receptor desensitization as seen in the MCP-1 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%