G-CSF drives a posttraumatic immune program that protects the host from infection.
Traumatic injury is generally considered to have a suppressive effect on the immune system, resulting in increased susceptibility to infection. Paradoxically, we found that thermal injury to the skin induced a robust time-dependent protection of mice from a lethal Klebsiella pneumoniae pulmonary challenge. The protective response was neutrophil dependent and temporally associated with a systemic increase in neutrophils resulting from a reprioritization of hematopoiesis toward myeloid lineages. A prominent and specific activation of STAT3 in the bone marrow preceded the myeloid shift in that compartment, in association with durable increases in STAT3 activating serum cytokines G-CSF and IL-6. Neutralization of the postburn increase in serum G-CSF largely blocked STAT3 activation in marrow cells, reversing the hematopoietic changes and systemic neutrophilia. Daily administration of rG-CSF was sufficient to recapitulate the changes induced by injury including hematopoietic reprioritization and protection from pulmonary challenge with K. pneumoniae. Analysis of posttraumatic gene expression patterns in humans reveals that they are also consistent with a role for G-CSF as a switch that activates innate immune responses and suppresses adaptive immune responses. Our findings suggest that the G-CSF STAT3 axis constitutes a key protective mechanism induced by injury to reduce the risk for posttraumatic infection.
Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267;
Jason C
JC
Gardner
John G
JG
Noel
Nikolaos M
NM
Nikolaidis
Rebekah
R
Karns
Bruce J
BJ
Aronow
Cora K
CK
Ogle
Francis X
FX
McCormack
D056704:Adaptive Immunity; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002056:Burns / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000276:immunology*; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D007710:Klebsiella Infections / Q000097:blood / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D007711:Klebsiella pneumoniae / Q000276:immunology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000097:blood / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor