Functional analysis of monocyte subsets in surgical sepsis

Background: Sepsis still remains a major cause of death after surgery. Impaired monocyte (M phi) function and disruption of monocyte (M phi)/T-cell interaction were shown to be crucial for the development of septic complications in these patients. It was the objective of the study to assess more insights in M phi behavior in surgical sepsis by means of analysis of Fc receptor- and human leukocyte antigen DR (HLA-DR) expression in M phi subsets, and to evaluate the kinetics of these changes. Methods: In a prospective study, 20 septic patients and 10 healthy control subjects were included. Peripheral M phi were isolated on consecutive days after onset of sepsis, and FcR positive (FcR+) and negative (FcR-) subsets were separated by resetting with antibody-coated human erythrocytes. Cell surface receptor expression and in vitro cytokine production were used to determine the clinical importance of these subsets. Results: A significant monocytosis (3.5-fold; p < 0.01) and suppression of HLA-DR receptor expression (35%, p < 0.01) which correlate with sepsis severity and outcome could be demonstrated. There was a significant increase of FcR+ subsets in sepsis compared with control subjects (60% vs. 24%; p < 0.05), In vitro stimulation of M phi subsets and peripheral blood mononuclear cells revealed suppressed interferon-gamma synthesis (p < 0.05 up to 0.01) from day 1 to day 5, elevated neopterin release (p < 0.05) on day 14 and increased synthesis rates of proinflammatory cytokines (e.g., interleukin-1 beta); p < 0.05) predominantly in FcR+ subsets. Conclusions: Sepsis results in a significant monocytosis and suppression of HLA-DR receptor expression, which are correlating with sepsis severity and outcome. A significant shift toward FcR+ M phi subsets can be found. This subpopulation resembles the previously described "angry macrophage" that is characterized by high proinflammatory cytokine synthesis and suppressed antigen presentation and that contributes to a disruption of adequate M phi/T-cell interaction, rendering the host anergic toward opportunistic infections. The extend of HLA-DR suppression and the shift toward FcR+ M phi might characterize a high risk patient subpopulation, which could benefit from immunomodulatory strategies.