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Novel chemokine responsiveness and mobilization of neutrophils during sepsis

Cecilia L Speyer1, Hongwei Gao, Nicholas J Rancilio

  • 1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.

The American Journal of Pathology
|December 8, 2004
PubMed

Insights

Sepsis changes how neutrophils respond to CC chemokines. Neutrophils from septic mice bind and move towards monocyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha, unlike in other lung inflammation models.

Area of Science:

  • Immunology
  • Cell Biology
  • Pathophysiology

Background:

  • Neutrophils (PMN) typically do not respond to CC chemokines like monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1 alpha (MIP-1 alpha).
  • Lung neutrophil accumulation after lipopolysaccharide (LPS) instillation in rodents is independent of MCP-1 and MIP-1 alpha.

Purpose of the Study:

  • To investigate the altered responsiveness of blood neutrophils to CC chemokines during sepsis.
  • To determine the role of CC chemokine receptors in neutrophil trafficking and cytokine release in a sepsis model.

Main Methods:

  • Induction of sepsis using cecal ligation and puncture (CLP) in rodents.
  • Assessment of neutrophil CC chemokine receptor expression and chemokine binding.
  • Chemotaxis assays for neutrophils in response to MCP-1 and MIP-1 alpha.
  • Evaluation of myeloperoxidase (MPO) activity in lung tissue.
  • Analysis of serum interleukin-6 (IL-6) levels in wild-type (WT) and CCR2 knockout (CCR2(-/-)) mice.

Main Results:

  • Neutrophils from CLP rodents, but not sham controls, expressed CC chemokine receptors and responded to MCP-1 and MIP-1 alpha.
  • Lung MPO activity in CLP mice was significantly reduced in CCR2(-/-) mice or WT mice treated with anti-MCP-1/MIP-1 alpha antibodies.
  • Increased serum IL-6 levels in CLP mice were dependent on CCR2, MCP-1, and MIP-1 alpha.
  • Incubation of CLP neutrophils with MCP-1 or MIP-1 alpha induced IL-6 release.

Conclusions:

  • Sepsis induces a fundamental shift in blood neutrophil behavior, enabling functional responses to CC chemokines.
  • The CCR2-MCP-1/MIP-1 alpha axis plays a critical role in neutrophil recruitment and IL-6 production during sepsis.
  • These findings highlight a novel mechanism of neutrophil trafficking and activation in the context of systemic infection.

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