Novel chemokine responsiveness and mobilization of neutrophils during sepsis.
Blood neutrophils (PMN) are usually unresponsive to CC chemokines such as monacyte chemotactic protein-1 and macrophage inflammatory protein-1 alpha. In rodents, the lung buildup of PMN as determined by myeloperoxidase (MPO) activity after airway instillation of bacterial lipopolysaccharide (LPS) was independent of MCP-1 and MIP-1 alpha. In striking contrast, during sepsis following cecal ligation and puncture (CLP), blood PMN demonstrated mRNA for CC chemokine receptors. Furthermore, PMN from CLP, but not from sham rodents, bound MCP-1 and MIP-1 alpha and responded chemotactically in vitro to both MCP-1 and MIP-1 alpha. In CCR2(-/-) mice or WT mice treated in vivo with antibodies to either MCP-1 or MIP-1 alpha, MPO activity was greatly attenuated in CLP animals. In CLP mice, increased serum IL-6 levels were found to be dependent on CCR2, MCP-1, and MIP-1 alpha. When PMN from CLP rodents were incubated in vitro with either MCP-1 or MIP-1 alpha, release of IL-6 was also shown. These findings suggest that sepsis fundamentally alters the trafficking of PMN into the lung in a manner that now engages functional responses to CC chemokines.
Speyer
Cecilia L
CL
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-0602, USA.
Gao
Hongwei
H
Rancilio
Nicholas J
NJ
Neff
Thomas A
TA
Huffnagle
Gary B
GB
Sarma
J Vidya
JV
Ward
Peter A
PA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002432:Cecum / Q000293:injuries; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D054407:Chemokine CCL4; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D009195:Peroxidase