Heat shock proteins (HSPs) require no adjuvant to confer immunogenicity to bound peptides, as if they possessed an intrinsic "danger" signature. To understand the proinflammatory nature of HSP, we analyzed signaling induced by human and chlamydial HSP60. We show that both HSP60s activate the stress-activated protein kinases p38 and JNK1/2, the mitogen-activated protein kinases ERK1/2, and the I-kappaB kinase (IKK). Activation of JNK and IKK proceeds via the Toll/IL-1 receptor signaling pathway involving MyD88 and TRAF6. Human fibroblasts transfected with TLR2 or TLR4 plus MD-2 gain responsiveness to HSP60, while TLR2- or TLR4-defective cells display impaired responses. Initiation of signaling requires endocytosis of HSP60 that is effectively inhibited by serum component(s). The results revealed that adjuvanticity of HSP60 operates similar to that of classical pathogen-derived ligands.
"Several DAMPs are released after CNS injury and are known ligands for a range of TLRs (Table 1). These include HMGB1, heat-shock proteins (HSP60 and HSP70), degradation products of the ECM (hyaluronic acid, fibronectin) and nucleic acids such as mRNA and miRNAs that are released passively from necrotic cells (Asea et al., 2002; Demarco et al., 2005; Kariko et al., 2004; Li et al., 2001; Ohashi et al., 2000; Okamura et al., 2001; Park et al., 2004; Smiley et al., 2001; Termeer et al., 2002; Vabulas et al., 2001, 2002; Yu et al., 2006). Mitochondrial DNA and proteins also act as DAMPs, particularly mtDNA and N-formyl peptides (Zhang et al., 2010) (Table 1). "
[Show abstract][Hide abstract] ABSTRACT: Pattern recognition receptors (PRRs) are part of the innate immune response and were originally discovered for their role in recognizing pathogens by ligating specific pathogen associated molecular patterns (PAMPs) expressed by microbes. Now the role of PRRs in sterile inflammation is also appreciated, responding to endogenous stimuli referred to as “damage associated molecular patterns” (DAMPs) instead of PAMPs. The main families of PRRs include Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-like receptors (RLRs), AIM2-like receptors (ALRs), and C-type lectin receptors. Broad expression of these PRRs in the CNS and the release of DAMPs in and around sites of injury suggest an important role for these receptor families in mediating post-injury inflammation. Considerable data now show that PRRs are among the first responders to CNS injury and activation of these receptors on microglia, neurons, and astrocytes triggers an innate immune response in the brain and spinal cord. Here we discuss how the various PRR families are activated and can influence injury and repair processes following CNS injury.
[Show abstract][Hide abstract] ABSTRACT: Protein quality control is essential in all organisms and regulated by the proteostasis network (PN) and cell stress response pathways that maintain a functional proteome to promote cellular health. In this review, we describe how metazoans employ multiple modes of cell-nonautonomous signaling across tissues to integrate and transmit the heat-shock response (HSR) for balanced expression of molecular chaperones. The HSR and other cell stress responses such as the unfolded protein response (UPR) can function autonomously in single-cell eukaryotes and tissue culture cells; however, within the context of a multicellular animal, the PN is regulated by cell-nonautonomous signaling through specific sensory neurons and by the process of transcellular chaperone signaling. These newly identified forms of stress signaling control the PN between neurons and nonneuronal somatic tissues to achieve balanced tissue expression of chaperones in response to environmental stress and to ensure that metastable aggregation-prone proteins expressed within any single tissue do not generate local proteotoxic risk. Transcellular chaperone signaling leads to the compensatory expression of chaperones in other somatic tissues of the animal, perhaps preventing the spread of proteotoxic damage. Thus, communication between subcellular compartments and across different cells and tissues maintains proteostasis when challenged by acute stress and upon chronic expression of metastable proteins. We propose that transcellular chaperone signaling provides a critical control step for the PN to maintain cellular and organismal health span.
Genes & Development 07/2014; 28(14):1533-1543. DOI:10.1101/gad.241125.114 · 10.80 Impact Factor
"Following signal binding, TLRs activate signaling components to initiate different types of immune biological responses. For example, TLR1-TLR2, TLR2-TLR6, and TLR5 induce mainly inflammatory cytokines, whereas TLR3 and TLR4 induce both type I interferon (IFN-I) and inflammatory cytokine Endogenous ligands Hsp60 ( Vabulas et al., 2001 ) Hsp70 ( Vabulas et al., 2002a ) Gp96 ( Vabulas et al., 2002b ) HSPB8 ( Roelofs et al., 2006 ) α -Crystalline ( Roelofs et al., 2006 ) Fibronectin (extra domain A) Hyaluronic acid ( Termeer et al., 2002 ; Jiang et al., 2005 ) Heparan sulfate ( Johnson et al., 2002 ) Fibrinogen ( Smiley et al., 2001 ) Surfactant-protein A ( Guillot et al., 2002 ) HMGB1 protein ( Park et al., 2004 ) β -defensin ( Biragyn et al., 2002 ) "
[Show abstract][Hide abstract] ABSTRACT: Abstract The interaction between the immune and nervous systems suggests invaluable mechanisms for several pathological conditions, especially neurodegenerative disorders. Multiple sclerosis (MS) is a potentially disabling chronic autoimmune disease, characterized by chronic inflammation and neurodegenerative pathology of the central nervous system. Toll-like receptors (TLRs) are an important family of receptors involved in host defense and in recognition of invading pathogens. The role of TLRs in the pathogenesis of autoimmune disorders such as MS is only starting to be uncovered. Recent studies suggest an ameliorative role of TLR3 and a detrimental role of other TLRs in the onset and progression of MS and experimental autoimmune encephalomyelitis, a murine model of MS. Thus, modulating TLRs can represent an innovative immunotherapeutic approach in MS therapy. This article outlines the role of these TLRs in MS, also discussing TLR-targeted agonist or antagonists that could be used in the different stages of the disease.
Reviews in the neurosciences 06/2014; 25(5). DOI:10.1515/revneuro-2014-0026 · 3.33 Impact Factor
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