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Summary: The discovery of toll‐like receptors (TLRs) and the subsequent recognition that endogenous nucleic acids (NAs) could serve as TLR ligands have led to essential insights into mechanisms of healthy immune responses as well as pathogenic mechanisms relevant to systemic autoimmune and inflammatory diseases. In systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis, NA‐containing immune complexes serve as TLR ligands, with distinct implications depending on the additional immune stimuli available. Plasmacytoid dendritic cells (pDCs), the robust producers of type I interferon (IFN‐I), are providing critical insights relevant to TLR‐mediated healthy immune responses and tissue repair, as well as generation of inflammation, autoimmunity and fibrosis, processes central to the pathogenesis of many autoimmune diseases. In this review, we describe recent data characterizing the role of platelets and NA‐binding chemokines in modulation of TLR signaling in pDCs, as well as implications for how the IFN‐I products of pDCs contribute to the generation of inflammation and wound healing responses by monocyte/macrophages. Chemokine modulators of TLR‐mediated B cell tolerance mechanisms and interactions between TLR signaling and metabolic pathways are also considered. The modulators of TLR signaling and their contribution to the pathogenesis of systemic autoimmune diseases suggest new opportunities for identification of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Regulation of the profile and magnitude of toll-like receptor (TLR) responses is important for effective host defense against infections while minimizing inflammatory toxicity. The chemokine CXCL4 regulates the TLR8 response to amplify inflammatory gene and inflammasome activation while attenuating the interferon (IFN) response in primary monocytes. In this study, we describe an unexpected role for the kinase RIPK3 in suppressing the CXCL4 + TLR8–induced IFN response and providing signal 2 to activate the NLRP3 inflammasome and interleukin (IL)-1 production in primary human monocytes. RIPK3 also amplifies induction of inflammatory genes such as TNF, IL6, and IL1B while suppressing IL12B. Mechanistically, RIPK3 inhibits STAT1 activation and activates PI3K-Akt–dependent and XBP1- and NRF2-mediated stress responses to regulate downstream genes in a dichotomous manner. These findings identify new functions for RIPK3 in modulating TLR responses and provide potential mechanisms by which RIPK3 plays roles in inflammatory diseases and suggest targeting RIPK3 and XBP1- and NRF2-mediated stress responses as therapeutic strategies to suppress inflammation while preserving the IFN response for host defense. RIPK3 modulates CXCL4 and TLR8 costimulation of human monocytes by augmenting inflammasome and inflammatory gene activation, while attenuating the interferon response. [ABSTRACT FROM AUTHOR]

Inhibitors of the immunoproteasome (i-20S) have shown promise in mouse models of autoimmune diseases and allograft rejection. In this study, we used a novel inhibitor of the immunoproteasome, PKS3053, that is reversible, noncovalent, tight-binding, and highly selective for the b5i subunit of the i-20S to evaluate the role that i-20S plays in regulating immune responses in vitro and in vivo. In contrast to irreversible, less-selective inhibitors, PKS3053 did not kill any of the primary human cell types tested, including plasmacytoid dendritic cells, conventional dendritic cells, macrophages, and T cells, all of which expressed genes encoding both the constitutive proteasome (c-20S) and i-20S. PKS3053 reduced TLR-dependent activation of plasmacytoid dendritic cells, decreasing their maturation and IFN-a response and reducing their ability to activate allogenic T cells. In addition, PKS3053 reduced T cell proliferation directly and inhibited TLR-mediated activation of conventional dendritic cells and macrophages. In a mouse model of skin injury that shares some features of cutaneous lupus erythematosus, blocking i-20S decreased inflammation, cellular infiltration, and tissue damage. We conclude that the immunoproteasome is involved in the activation of innate and adaptive immune cells, that their activation can be suppressed with an i-20S inhibitor without killing them, and that selective inhibition of β5i holds promise as a potential therapy for inflammatory skin diseases such as psoriasis, cutaneous lupus erythematosus, and systemic sclerosis. [ABSTRACT FROM AUTHOR]

Objective: Subchondral bone modifications occur early in the development of osteoarthritis (OA). The level of bone resorption might impact cartilage remodeling. We therefore assessed the in vivo and in vitro effects of targeting bone resorption in OA and cartilage metabolism. Methods: OA was induced by meniscectomy (MNX) in ovariectomized osteopenic mice (OP) treated with estradiol (E2), pamidronate (PAM), or phosphate buffered saline (PBS) for 6 weeks. We assessed the subchondral bone and cartilage structure and the expression of cartilage matrix proteases. To assess the involvement of bone soluble factors in cartilage metabolism, supernatant of human bone explants pre-treated with E2 or PAM were transferred to cartilage explants to assess proteoglycan release and aggrecan cleavage. OPG/RANKL mRNA expression was assessed in bone explants by realtime quantitative PCR. The role of osteoprotegerin (OPG) in the bone-cartilage crosstalk was tested using an OPG neutralizing antibody. Results: Bone mineral density of OP mice and osteoclast number were restored by E2 and PAM (p<0.05). In OP mice, E2 and PAM decreased ADAMTS-4 and -5 expression, while only PAM markedly reduced OA compared to PBS (2.0±0.63 vs 5.2±0.95; p<0.05). OPG/RANKL mRNA was increased in human bone explants treated with both drugs (2.2-3.7-fold). Moreover, supernatants from bone explants cultured with E2 or PAM reduced aggrecan cleavage and cartilage proteoglycan release (7368.0% and 80±22% of control, respectively, p<0.05). This effect was reversed with osteoprotegerin blockade. Conclusion: The inhibition of bone resorption by pamidronate in osteopenic mice alleviates the histological OA score with a reduction in the expression of aggrecanases. Bone soluble factors, such as osteoprotegerin, impact the cartilage response to catabolic factors. This study further highlights the importance of subchondral bone in the regulation of joint cartilage damage in OA. [ABSTRACT FROM AUTHOR]