Dysfunctional expansion of immature granulocytes in sepsis survivors.

Abstract

Abstract Sepsis is one of the leading causes of death worldwide. Surprisingly, increased mortality persists for years in sepsis survivors. This project investigated the contribution of myeloid cells to immune impairment in sepsis surviving mice. Sepsis was induced by cecal ligation and puncture (CLP). Sepsis survivors (2 weeks post-surgery) had significant increases in the CD11b+ Ly6Chigh and CD11b+ Ly6Clow myeloid populations in spleen, bone marrow and blood compared to controls. The expanded CD11b+ Ly6C populations in survivors were F4/80 negative. More CD11b+ Ly6C cells expressed the chemokine receptors CX3CR1 and CCR2, and the adhesion molecule CD62L. CD11b+ Ly6C populations in survivors also had higher levels of the mannose receptor CD206, Mer tyrosine kinase and the inhibitory collagen receptor LAIR-1; they appeared to be M2 like macrophages with presumed immune suppressive activity. Approximately 12% of the CD11b+Ly6Chigh population were CD115+ monocytes/macrophages, while the CD11b+ Ly6Clow comprised mainly immature granulocytes. CD11b+ Ly6Clow granulocytes in sepsis survivors had significantly reduced phagocytic activity compared to controls. A significant reduction in CD11b+ Ly6Clow granulocytes after LPS treatment was observed in controls but not survivors. Importantly, survivors had diminished serum production of TNF in response to endotoxin challenge, even though CD11b+ Ly6C granulocytes from the same mice produced comparable intracellular levels of TNF. In summary, our data indicate impaired cell exit and cytokine secretion, which is in part due to altered cell surface properties. This dysfunctional expansion of immature granulocytes may contribute to the impaired immune response in sepsis survivors.