LACC1 genetic variants are associated with multiple immune-mediated diseases. However, laccase domain containing-1 (LACC1) functions are incompletely defined. We find that upon stimulation of the pattern-recognition receptor (PRR) NOD2, LACC1 localizes to the endoplasmic reticulum (ER) and forms a complex with ER-stress sensors. All three ER-stress branches, PERK, IRE1α, and ATF6, are required for NOD2-induced signaling, cytokines, and antimicrobial pathways in human macrophages. LACC1, and its localization to the ER, is required for these outcomes. Relative to wild-type (WT) LACC1, transfection of the common Val254 and rare Arg284 immune-mediated disease-risk LACC1 variants into HeLa cells and macrophages, as well as macrophages from LACC1 Val254 carriers, shows reduced NOD2-induced ER stress-associated outcomes; these downstream outcomes are restored by rescuing ER stress. Therefore, we identify ER stress to be essential in PRR-induced outcomes in macrophages, define a critical role for LACC1 in these ER stress-dependent events, and elucidate how LACC1 disease-risk variants mediate these outcomes.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Human osteoarthritis (OA) has been reclassified as a systemic musculoskeletal disorder involving activation of the innate and adaptive immune systems. Elevated pro-inflammatory cytokines may serve a key function in the development of the disease. 1,25-Dihydroxyvitamin D3 and dexamethasone (vitD3/Dex) may inhibit inflammation by acting on tolerogenic dendritic cells (tolDCs) in chronic inflammatory conditions. In the present study, DCs were isolated from peripheral blood mononuclear cells of patients with OA. DCs expressing high levels of co-stimulatory molecules maintain a tolerogenic phenotype under stimulation with LPS, which promotes DC maturation to generate tolDCs. When vitD3/Dex were added in the current study, the tolDCs produced pro-inflammatory cytokines, including low levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-10, and high levels of transforming growth factor-β. However, when vitD3/Dex were added to DCs without LPS stimulation, the levels of IL-10 were high. DCs with LPS stimulation increased the percentage of T-cells that produced IFN-γ and IL-17 and DCs with vitD3/Dex treatment alone increased the percentage of T-cells that produced IL-10 and FoxP3. However, those cytokines decrease in DCs co-processed with LPS and vitD3/Dex. The IL-10 release by the stimulated T cells was indicated to repress autologous T cell proliferation via soluble IL-10 and cell-cell contact. Furthermore, tolDCs and regulatory T cells suppressed matrix metalloproteinase (MMP)-1 and MMP-13 secretion by chondrocytes. Additionally, Akt and p38 mitogen-activated protein kinase signaling were demonstrated to be involved in the regulatory effects of Dec and vitD3 in DCs. The present findings suggest a novel mechanism underlying the beneficial effects of tolDCs, particularly in association with the pathogenesis of OA.