Damage-associated molecular patterns (DAMPs) are endogenous danger molecules that are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors (PRRs). Although DAMPs contribute to the host's defense, they promote pathological inflammatory responses. Recent studies have suggested that various DAMPs, such as high-mobility group box 1 (HMGB1), S100 proteins, and heat shock proteins (HSPs), are increased and considered to have a pathogenic role in inflammatory diseases. Here, we review current research on the role of DAMPs in inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, atherosclerosis, Alzheimer's disease, Parkinson's disease, and cancer. We also discuss the possibility of DAMPs as biomarkers and therapeutic targets for these diseases.
IntroductionOsteoarthritis (OA) is a degenerative disease characterized by cartilage breakdown in the synovial joints. The presence of low-grade inflammation in OA joints is receiving increasing attention, with synovitis shown to be present even in the early stages of the disease. How the synovial inflammation arises is unclear, but proteins in the synovial fluid of affected joints could conceivably contribute. We therefore surveyed the proteins present in OA synovial fluid and assessed their immunostimulatory properties.MethodsWe used mass spectrometry to survey the proteins present in the synovial fluid of patients with knee OA. We used a multiplex bead-based immunoassay to measure levels of inflammatory cytokines in serum and synovial fluid from patients with knee OA and from patients with rheumatoid arthritis (RA), as well as in sera from healthy individuals. Significant differences in cytokine levels between groups were determined by significance analysis of microarrays, and relations were determined by unsupervised hierarchic clustering. To assess the immunostimulatory properties of a subset of the identified proteins, we tested the proteins' ability to induce the production of inflammatory cytokines by macrophages. For proteins found to be stimulatory, the macrophage stimulation assays were repeated by using Toll-like receptor 4 (TLR4)-deficient macrophages.ResultsWe identified 108 proteins in OA synovial fluid, including plasma proteins, serine protease inhibitors, proteins indicative of cartilage turnover, and proteins involved in inflammation and immunity. Multiplex cytokine analysis revealed that levels of several inflammatory cytokines were significantly higher in OA sera than in normal sera, and levels of inflammatory cytokines in synovial fluid and serum were, as expected, higher in RA samples than in OA samples. As much as 36% of the proteins identified in OA synovial fluid were plasma proteins. Testing a subset of these plasma proteins in macrophage stimulation assays, we found that Gc-globulin, α1-microglobulin, and α2-macroglobulin can signal via TLR4 to induce macrophage production of inflammatory cytokines implicated in OA.ConclusionsOur findings suggest that plasma proteins present in OA synovial fluid, whether through exudation from plasma or production by synovial tissues, could contribute to low-grade inflammation in OA by functioning as so-called damage-associated molecular patterns in the synovial joint.
The mammalian SWI/SNF complex is an evolutionarily conserved ATP-dependent chromatin remodeling complex that consists of nine or more components. SRG3, a murine homologue of yeast SWI3, Drosophila MOIRA, and human BAF155, is a core component of the murine SWI/SNF complex required for the regulation of transcriptional processes associated with development, cellular differentiation, and proliferation. Here we report that SRG3 interacts directly with other components of the mammalian SWI/SNF complex such as SNF5, BRG1, and BAF60a. The SWIRM domain and the SANT domain were required for SRG3-SNF5 and SRG3-BRG1 interactions, respectively. In addition, SRG3 stabilized SNF5, BRG1, and BAF60a by attenuating their proteasomal degradation, suggesting its general role in the stabilization of the SWI/SNF complex. Such a stabilization effect of SRG3 was not only observed in the in vitro cell system, but also in cells isolated from SRG3 transgenic mice or knock-out mice haploinsufficient for the Srg3 gene. Taken together, these results suggest the critical role of SRG3 in the post-transcriptional stabilization of the major components of the SWI/SNF complex.The mammalian SWI/SNF complexes are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which use the energy of ATP hydrolysis to mobilize nucleosomes and remodel chromatin structure (1, 2). These complexes play important roles in transcriptional regulation, thereby controlling diverse cellular processes including proliferation, differentiation, cell death, and tumorigenesis (3-6). The mammalian SWI/SNF complexes are multisubunit complexes that consist of invariant core components and variable components (7). The subunit diversity of mammalian SWI/ SNF complexes suggests that different complexes might have tissue-specific roles during development (8). The core components of the mammalian SWI/SNF complexes are BRG1 or hBRM, SNF5/INI1/BAF47, BAF155/SRG3, and BAF170 (9). BRG1 and BRM are DNA-dependent ATPase homologous to yeast SWI2/SNF2. Biochemical experiments have shown that although BRG1 or BRM alone can remodel nucleosomal arrays, the addition of other core components (BAF155, BAF170, and SNF5) to BRG1 stimulates the remodeling activity of BRG1 at a rate that is comparable with the entire complex in vitro (10).Human SNF5 was initially identified by the yeast two-hybrid system through its interaction with human immunodeficiency virus type 1 integrase (11). It was shown that human SNF5 interacts with c-Myc, thereby enhancing c-Myc-mediated transactivation by recruiting the SWI/SNF complex to the E-box (12). Furthermore, human SNF5 is known as a tumor suppressor in atypical teratoid and malignant rhabdoid tumors and the majority of these tumors have deletion or point mutations in SNF5 leading to disruption of normal function of SNF5 (13,14).Srg3 (Swi3-related gene), a murine homologue of yeast Swi3, Drosophila Moira, and human Baf155, was initially isolated as a gene highly expressed in the thymus but at a low level in the peripheral lymphoid organ (15). It...
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