Abstract
Lipoteichoic acid (LTA) is a Gram-positive cell surface molecule that is found in both a cell-bound form and cell-free form in the host during an infection. Hemoglobin (Hb) can synergize with LTA, a TLR2 ligand, to potently activate macrophage innate immune responses in a TLR2- and TLR4-dependent way. At low levels of LTA, the presence of Hb can result in a 200-fold increase in the secretion of IL-6 following macrophage activation. Six hours after activation, the macrophage genes that are most highly up-regulated by LTA plus Hb activation compared to LTA alone are cytokines, chemokines, receptors and interferon-regulated genes. Several of these genes exhibit a unique TLR4-dependent increase in mRNA levels that continued to rise more than eight hours after stimulation. This prolonged increase in mRNA levels could be the result of an extended period of NF-κB nuclear localization and the concurrent absence of the NF-κB inhibitor, IκBα, after stimulation with LTA plus Hb. Dynasore inhibition experiments indicate that an endocytosis-dependent pathway is required for the TLR4-dependent up-regulation of IL-6 secretion following activation with LTA plus Hb. In addition, interferon-β mRNA is present after activation with LTA plus Hb, suggesting that the TRIF/TRAM-dependent pathway may be involved. Hb alone can elicit the TLR4-dependent secretion of TNF-α from macrophages, so it may be the TLR4 ligand. Hb also led to secretion of high mobility group box 1 protein (HMGB1), which synergized with LTA to increase secretion of IL-6. The activation of both the TLR2 and TLR4 pathways by LTA plus Hb leads to an enhanced innate immune response.
Highlights
The mammalian innate immune system is responsible for the initial response to invading pathogens of various types
Synergism between Hb and TLR2 Ligands We have previously shown that activating either murine peritoneal macrophages or human blood cells with Lipoteichoic acid (LTA) plus Hb significantly enhanced the secretion of IL-6 when compared to activating with LTA alone, even though incubation with Hb alone resulted in no detectable secretion of IL-6 [25]
Macrophages were more sensitive to both lipopeptides, on either a weight or molar basis, but the maximum response and synergy with Hb were greater when cells were stimulated with LTA
Summary
The mammalian innate immune system is responsible for the initial response to invading pathogens of various types. Responses to some cell surface components of Gram-positive bacteria, such as lipoproteins (including synthetic lipopeptides such as Pam2CSK4 and Pam3CSK4) and lipoteichoic acids (LTAs), require TLR2/TLR1 or TLR2/TLR6 heterodimers [10] and, in some cases, CD36 [11]. These TLRs are expressed on the plasma membrane and trigger unique signal transduction pathways both from the surface of macrophages, as well as from endocytic vesicles within the cell [12,13,14]
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