Hemophagocytic Macrophages in Murine Typhoid Fever Have an Anti-Inflammatory Phenotype

Abstract

Histiocytes are white blood cells of the monocytic lineage and include macrophages and dendritic cells. In patients with a variety of infectious and noninfectious inflammatory disorders, histiocytes can engulf nonapoptotic leukocytes and nonsenescent erythrocytes and thus become hemophagocytes. We report here the identification and characterization of splenic hemophagocytes in a natural model of murine typhoid fever. The development of a flow-cytometric method allowed us to identify hemophagocytes based on their greater than 6N (termed 6N؉) DNA content. Characterization of the 6N؉ population from infected mice showed that these cells consist primarily of macrophages rather than dendritic cells and contain T lymphocytes, consistent with hemophagocytosis. Most 6N؉ macrophages from Salmonella enterica serovar Typhimurium-infected mice contain intact DNA, consistent with hemophagocytosis. In contrast, most 6N؉ macrophages from control mice or mice infected with a different bacterial pathogen, Yersinia pseudotuberculosis, contain damaged DNA. Finally, 6N؉ splenic macrophages from S. Typhimuriuminfected mice express markers consistent with an anti-inflammatory M2 activation state rather than a classical M1 activation state. We conclude that macrophages are the predominant splenic hemophagocyte in this disease model but not in Y. pseudotuberculosis-infected mice. The anti-inflammatory phenotype of hemophagocytic macrophages suggests that these cells contribute to the shift from acute to chronic infection.

Increased Ferroportin-1 Expression and Rapid Splenic Iron Loss Occur with Anemia Caused by Salmonella enterica Serovar Typhimurium Infection in Mice

“…7), were observed in serum and were highest during the acute stage of infection. IL-4 was high early in infection and further increased by 3 weeks postinfection, consistent with a subacute, alternative activation state in select macrophage populations (41,42), including hemophagocytes (28). Thus, Salmonella-infected mice have a particularly strong proinflammatory response at 1 week postinfection that declines but remains significantly higher than that of control mice over the subsequent 3 weeks.…”

“…3) and in our prior studies (7,8,10,28). Sustained exogenous delivery of cytokines (IFN-␥ or IL-4) or a TLR9 agonist (CpG) promotes tissue hemophagocytosis and the development of anemia (42,51,52).…”

Replication of Salmonella enterica Serovar Typhimurium in Human Monocyte-Derived Macrophages

“…In mice, certain subsets of macrophages are the preferred sites of Salmonella Typhimurium survival and replication (25)(26)(27); however, its ability to survive and replicate in human macrophages is not well described. In human macrophage-like cell lines (THP-1 and U937), it appears to replicate less than in murine macrophage-like cell lines (RAW 264.7 and J774), and there are few reports describing its replication in human macrophages (28)(29)(30)(31).…”

Salmonella Infection Enhances Erythropoietin Production by the Kidney and Liver, Which Correlates with Elevated Bacterial Burdens

“…Hemophagocytic macrophages display an anti-inflammatory phenotype and appear to be permissive for Salmonella growth in a mouse model of chronic Salmonella infection (65). Thus, any increase in the number of hemophagocytes would be expected to enhance bacterial persistence in vivo.…”

“…However, it seems possible that CV1 would enhance erythrocyte uptake by macrophages and therefore increase the number of hemophagocytes in the spleen. Since hemophagocytes have an anti-inflammatory phenotype (65), any expansion in the number of these cells should provide a niche for enhanced bacterial growth. Mice infected with Salmonella also show a loss of iron from the spleen and high levels of expression of ferroportin-1 on macrophages (66), which should limit the availability of iron for intracellular bacterial growth.…”