Bacterial Stimulation of Toll-Like Receptor 4 Drives Macrophages To Hemophagocytose

Abstract

During acute infection with bacteria, viruses or parasites, a fraction of macrophages engulf large numbers of red and white blood cells, a process called hemophagocytosis. Hemophagocytes persist into the chronic stage of infection and have an anti-inflammatory phenotype. Salmonella enterica serovar Typhimurium infection of immunocompetent mice results in acute followed by chronic infection, with the accumulation of hemophagocytes. The mechanism(s) that triggers a macrophage to become hemophagocytic is unknown, but it has been reported that the proinflammatory cytokine gamma interferon (IFN-␥) is responsible. We show that primary macrophages become hemophagocytic in the absence or presence of IFN-␥ upon infection with Gram-negative bacterial pathogens or prolonged exposure to heat-killed Salmonella enterica, the Gram-positive bacterium Bacillus subtilis, or Mycobacterium marinum. Moreover, conserved microbe-associated molecular patterns are sufficient to stimulate macrophages to hemophagocytose. Purified bacterial lipopolysaccharide (LPS) induced hemophagocytosis in resting and IFN-␥-pretreated macrophages, whereas lipoteichoic acid and synthetic unmethylated deoxycytidine-deoxyguanosine dinucleotides, which mimic bacterial DNA, induced hemophagocytosis only in IFN-␥-pretreated macrophages. Chemical inhibition or genetic deletion of Toll-like receptor 4, a pattern recognition receptor responsive to LPS, prevented both Salmonella-and LPS-stimulated hemophagocytosis. Inhibition of NF-B also prevented hemophagocytosis. These results indicate that recognition of microbial products by Toll-like receptors stimulates hemophagocytosis, a novel outcome of prolonged Toll-like receptor signaling, suggesting hemophagocytosis is a highly conserved innate immune response.

Siderophores in Iron Metabolism: From Mechanism to Therapy Potential

“…2A, #3); this is beneficial for Salmonella , an intracellular pathogen, as it maintains the intracellular iron pool. Furthermore, Salmonella can stimulate macrophages to specifically phagocytose erythrocytes in an effort to acquire more iron [36] through Toll-like receptor 4 (TLR4) signaling [37] (Key Figure, Fig. 2A, #4).…”

Salmonella finds a way: Metabolic versatility of Salmonella enterica serovar Typhimurium in diverse host environments

“…S. Typhimurium can also be found in other M2-like macrophage subtypes, such as granuloma macrophages, which share many characteristics with M2 macrophages but have distinct cell markers and functions [4]. Additionally, S. Typhimurium infects hemophagocytic macrophages, macrophages that have ingested nonapoptotic cells [5,6]. Hemophagocytic macrophages express M2 markers and produce lower levels of inducible nitric oxide synthase (iNOS) [7].…”

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

“…Type I interferons may also induce the exposure of phosphatidylserine (PS) on the surface of erythrocytes and the expression of PS receptors on myeloid cells, triggering erythrophagocytosis upon infection with lymphocytic choriomeningitis virus (LCMV) [ 118 ]. Along with cytokines, activation of TLR4 also stimulates hemophagocytosis [ 119 ]. On the other side, the pathogen may also have an active role in inducing alterations in erythrocytes, to cause their phagocytosis.…”