G-CSF Drives a Posttraumatic Immune Program That Protects the Host from Infection

Abstract

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 post burn rise in serum G-CSF largely blocked STAT3 activation in marrow cells, reversing the hematopoietic changes and systemic neutrophilia. Daily administration of recombinant G-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 of post-traumatic infection.

Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis

“…Cytokines that are attenuated by NLRP12, in particular TNF, have been shown to enhance hematopoietic stem cell (HSC) expansion (2, 5, 10, 25). We therefore examined NLRP12-dependent production of selected cytokines and their receptors after RCI.…”

“…There is no single mechanism that has been defined for immune suppression in the response to traumatic injury, but hematopoietic stem cell (HSC) expansion and immune repopulation have been shown to be important factors (2, 5, 10, 25, 37). …”

STAT3 signaling in immunity

“…IFN-γ-dependent STAT3 inhibition is thought to be regulated via IFN-γ-responsive SOCS3 induction and subsequent inhibition of G-CSFR-STAT3-mediated proliferation within the GMP and common myeloid progenitor (CMP) populations [129]. Thus, cytokine-driven stimulation or inhibition of STAT3 activity in myeloid progenitors may be key to tailoring hematopoietic output, to meet unique demands upon the immune system during different infection or emergency conditions (Figure 3) [103,129,131]. …”

Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury

“…While the preponderance of animal studies have focused on the early (“SIRS”) immune response following injury, animal studies focused on the late immune response (the former CARS phase) have been infrequent. In addition, these studies have demonstrated significantly enhanced, immunopathogenic hyperinnate immune responses rather than the clinical picture of general immunosuppression.…”