Toll-Like Receptor 4 Mediates Tolerance in Macrophages Stimulated withToxoplasma gondii-Derived Heat Shock Protein 70

Abstract

Peritoneal macrophages (PMs) from toll-like receptor 4 (TLR4)-deficient and wild-type (WT) mice were responsive to recombinant Toxoplasma gondii-derived heat shock protein 70 (rTgHSP70) and natural TgHSP70 (nTgHSP70) in NO release, but those from TLR2-, myeloid differentiation factor 88 (MyD88)-, and interleukin-1R-associated kinase 4 (IRAK4)-deficient mice were not. Polymyxin B did not inhibit PM activation by TgHSP70 and nTgHSP70 from WT and TLR4-deficient mice, while it inhibited PM activation by lipopolysaccharide. Pretreatment of PMs from WT but not from TLR4-deficient mice with rTgHSP70 resulted in suppression of NO release on restimulation with rTgHSP70. Similarly, pretreatment of PMs from WT but not TLR4-deficient mice with nTgHSP70 resulted in suppression of NO release on restimulation with nTgHSP70. Polymyxin B did not inhibit rTgHSP70- and nTgHSP70-induced tolerance of PMs from TLR4-deficient mice. Furthermore, PMs from WT mice increased suppressor of cytokine-signaling-1 (SOCS-1) expression after restimulation with rTgHSP70, while those from TLR4-deficient mice did not. Phosphorylation of JNK and I-κBα occurred in rTgHSP70-induced tolerance of PMs from TLR4-deficient mice, but not in that from WT mice. These data indicated that TgHSP70 signaling mechanisms were mediated by TLR2, MyD88, and IRAK4, but not by TLR4. On the other hand, signaling of TgHSP70-induced tolerance was mediated by TLR4, and the expression of SOCS-1 suppressed the TLR2 signaling pathway

A MyD88–JAK1–STAT1 complex directly induces SOCS-1 expression in macrophages infected with Group A Streptococcus

“…Furthermore, studies have shown that other pathogens induce SOCS-1 protein expression, which would be particularly beneficial to pathogens infecting and replicating in macrophages. [9][10][11][12] We also found that viable GAS-induced SOCS-1 expression was much higher and occurred earlier in murine macrophages than in non-viable GAS infection. This observation revealed that some heatsensitive molecules of GAS were very important in inducing SOCS-1 protein expression.…”

“…It has been previously confirmed that SOCS-1 proteins regulate cytokine communication in macrophages, and microbes exploit the host SOCS system to evade immunity. [9][10][11][12]20 To investigate whether SOCS-1 proteins were produced in GAS-induced macrophages, we looked for SOCS-1 expression in GAS-infected RAW 264.7 cells, which is a well-described mouse macrophage model. The results demonstrated that the SOCS-1 mRNA level was elevated at 4 h after GAS infection and peaked at 6 h (reaching an approximate 12-fold induction).…”

“…For example, Toxoplasma gondii induces expression of SOCS-1, which contributes to the proliferation of the bacteria within the hostile environment of macrophages. 9,10 Mycobacteria and Burkholderia pseudomallei increase the expression of SOCS-1 in macrophages-a process that has been linked to immune escape. 11,12 IFN-b is clearly one of the major activators of SOCS-1.…”

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

“…Also, reactivationTgHSP70 in vivo induced expression of TgHSP70 during bradyzoite to tachyzoite interconversion [322] . Recombinant (rTgHSP70) and natural TgHSP70 stimulated the NO release by peritoneal macrophages via TRL2, MyD888 and IRAK4, but under restimulation, signaling of rTgHSP70-induced tolerance was mediated by TRL4 [323] . HSP70 has been shown to be a major immunomodulant antigen in parasitic and bacterial infections, and the preferred target of humoral and cell-mediated immune responses to infection [320,[323][324][325][326] .…”

“…Recombinant (rTgHSP70) and natural TgHSP70 stimulated the NO release by peritoneal macrophages via TRL2, MyD888 and IRAK4, but under restimulation, signaling of rTgHSP70-induced tolerance was mediated by TRL4 [323] . HSP70 has been shown to be a major immunomodulant antigen in parasitic and bacterial infections, and the preferred target of humoral and cell-mediated immune responses to infection [320,[323][324][325][326] . Barenco et al [321] found that in mice the TgHSP70 release into the bloodstream was dependent on the death of T. gondii tachyzoites mediated by the host immune response, whereas the increased TgHSP70 expression in the brain depended on the multiplication rate of the parasite.…”