Granulocyte-Macrophage Colony-Stimulating Factor Partially Restores Toll-LikeReceptor-Mediated Functional Responses of Monocytes in Septic Shock

Septic shock remains clinically challenging to manage. The dysregulated immune response seen in septic shock contributes to this complexity. However, biological response modifiers including the cytokine recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) might be important in managing both septicemia and septic shock. We hypothesized that ex vivo stimulation with rHuGM-CSF could restore functional and phenotypic responses of monocytes. The functional responses of complex whole blood and highly-enriched monocyte cultures were assessed from a panel of n=30 human study subjects (n=23, septic shock and n=7 healthy controls). Cultures were initially primed with rHuGM-CSF then stimulated with relevant toll-like receptor (TLR) ligands for short (4 h) or extended (48 h) time-periods. TLR-specific ligands included lipopolysaccharide (LPS, a surrogate of gram-negative bacterial infection) and double-stranded RNA (dsRNA, a surrogate of a viral infection). Endpoints included measurement of cell surface receptors by flow cytometry and cytokine secretion by multiplex bead-array technology. We found depressed expression of immune cell-surface markers on septic shock monocytes as compared to normal controls. However, a trend of partially restored cell surface expression of functionally important phenotypic markers on septic shock monocytes was associated with restored, or even augmented, cytokine secretion following rHuGM-CSF-priming and secondary stimulation with LPS or dsRNA. A dysregulated pattern of cell activation typically characterizes septic shock and may contribute to inadvertent immune suppression of monocytes. We have showed that rHuGM-CSF priming restored several important aspects of monocyte responsiveness to exogenous bacterial and viral stimuli. This approach could offer therapeutic utility that nonetheless requires empirical proof of concept.