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Adult onset Still disease (AOSD) is a systemic inflammatory disorder characterized by skin rash, spiking fever, arthritis, sore throat, lymphadenopathy, and hepatosplenomegaly. Although the etiology of this disease has not been fully clarified, both innate and acquired immune responses could contribute to its pathogenesis. Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity, as well as hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD. In innate immunity, activation of monocytes/macrophages might play central roles in the development of AOSD and macrophage activation syndrome (MAS), a severe life-threating complication of AOSD. Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern recognition receptors (PRRs) axis, and neutrophil extracellular traps (NETs)-DNA. These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1β and pro-IL-18 into mature forms. Thereafter, IL-1β and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD. We identified placenta-specific 8 (PLAC8) as a specifically increased molecule in monocytes of active AOSD, which correlated with serum levels of CRP, ferritin, IL-1β, and IL-18. Interestingly, PLAC8 could suppress the synthesis of pro-IL-1β and pro-IL-18 via enhanced autophagy; thus, PLAC8 seems to be a regulatory molecule in AOSD. These findings for the activation mechanisms of monocytes/macrophages could shed light on the pathogenesis and development of a novel therapeutic strategy for AOSD.

Objective\\n\\nInvariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide (α-GalCer). Glucose-6-phosphate isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-α and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by α-GalCer in GPI peptide-induced arthritis.\\nMethods\\n\\nArthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or α-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells.\\nResults\\n\\nα-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In α-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-γ, IL-2, and TNF-α produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and α-GalCer did not generate any cytokines even when these cells were co-cultured with APC from mice immunized with GPI alone. In vitro depletion of iNKT cells did not alter the suppressive effect of α-GalCer on CD4+ T cells.\\nConclusion\\n\\nα-GalCer significantly suppressed GPI peptide-induced arthritis through the suppression of GPI-specific CD4+ T cells.

TNFα-induced adipose-related protein (TIARP) is a six-transmembrane protein expressed on macrophages, neutrophils and synoviocytes. We reported recently that mice deficient in TIARP (TIARP −/− ) spontaneously develop arthritis and are highly susceptible to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effects of TIARP on neutrophils and fibroblast-like synoviocytes (FLS) have not been elucidated. We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP −/− mice. Arthritis in TIARP −/− mice transferred with K/BxN serum was significantly exacerbated compared with WT mice. We characterized the differences in neutrophils between wild-type (WT) and TIARP −/− mice by DNA microarray. Overexpression of CXCR1 and CXCR2 was noted in TIARP −/− neutrophils. Neutrophils of TIARP −/− mice showed strong migration activity, which was markedly facilitated by CXCL2 in vitro and in vivo . Moreover, enhanced production of CXCL2 and IL-6 and cell proliferation was noted in TIARP −/− TNFα-stimulated FLS. Blockade of IL-6R significantly attenuated serum-transferred TIARP −/− arthritis with diminished neutrophil recruitment in joints. Our findings suggested that TIARP independently down-regulated CXCL2 and IL-6 production by FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, with resultant reduction of neutrophil migration into arthritic joints.

Introduction Differentiation of T helper 17 cells is dependent on the expression of transcription retinoid-related orphan receptor gamma t (RORγt). The purpose of our study is to determine the role of RORγt expression in T cells on the development of collagen-induced arthritis (CIA). Methods CIA was induced in C57BL/6 and T cell-specific RORγt transgenic (RORγt Tg) mice. At day 10 post-1st-immunization, lymph node (LN) cells were cultured with type II collagen (CII), and the expression levels of various cytokines and transcription factors on CD4 + T cells were measured. Total cells or CD4 + cells of draining LN were harvested from each mouse group after CII-immunization and transferred into C57BL/6 mice, and then CIA was induced in recipient mice. The expression levels of RORγt and other surface antigens, and the production of cytokines were analyzed in forkhead box P3 (Foxp3) + regulatory T (Treg) cells. Foxp3 + Treg cells were analyzed for suppressive activity against proliferation of effector CD4 + T cells. Interlukin (IL)-10 neutralizing antibody was administrated in the course of CIA. Results CIA was significantly suppressed in RORγt Tg mice compared with C57BL/6 mice. RORγt expression and IL-17 production were significantly higher in CII-reactive CD4 + T cells from RORγt Tg mice. Arthritis was significantly attenuated in C57BL/6 mice recipient of cells from RORγt Tg mice. Most of Foxp3 + Treg cells expressed RORγt, produced IL-10 but not IL-17, and overexpressed CC chemokine receptor 6 (CCR6) and surface antigens related to the suppressive activity of Foxp3 + Treg cells in RORγt Tg mice. In vitro suppression assay demonstrated significant augmentation of the suppressive capacity of Foxp3 + Treg cells in RORγt Tg mice. CIA was exacerbated in both C57BL/6 mice and RORγt Tg mice by the treatment of anti-IL-10 antibody. Conclusion Our results indicated that RORγt overexpression in T cells protected against the development of CIA. The protective effects were mediated, at least in part, through the anti-inflammatory effects including high production of IL-10 of RORγt + Foxp3 + Treg cells.

TNFα-induced adipose-related protein (TIARP) is a six-transmembrane protein expressed on macrophages, neutrophils and synoviocytes. We reported recently that mice deficient in TIARP (TIARP−/−) spontaneously develop arthritis and are highly susceptible to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effects of TIARP on neutrophils and fibroblast-like synoviocytes (FLS) have not been elucidated. We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP−/− mice. Arthritis in TIARP−/− mice transferred with K/BxN serum was significantly exacerbated compared with WT mice. We characterized the differences in neutrophils between wild-type (WT) and TIARP−/− mice by DNA microarray. Overexpression of CXCR1 and CXCR2 was noted in TIARP−/− neutrophils. Neutrophils of TIARP−/− mice showed strong migration activity, which was markedly facilitated by CXCL2 in vitro and in vivo. Moreover, enhanced production of CXCL2 and IL-6 and cell proliferation was noted in TIARP−/− TNFα-stimulated FLS. Blockade of IL-6R significantly attenuated serum-transferred TIARP−/− arthritis with diminished neutrophil recruitment in joints. Our findings suggested that TIARP independently down-regulated CXCL2 and IL-6 production by FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, with resultant reduction of neutrophil migration into arthritic joints.

Differentiation of T helper 17 cells is dependent on the expression of transcription retinoid-related orphan receptor gamma t (ROR[gamma]t). The purpose of our study is to determine the role of ROR[gamma]t expression in T cells on the development of collagen-induced arthritis (CIA). CIA was induced in C57BL/6 and T cell-specific ROR[gamma]t transgenic (ROR[gamma]t Tg) mice. At day 10 post-1st-immunization, lymph node (LN) cells were cultured with type II collagen (CII), and the expression levels of various cytokines and transcription factors on CD4.sup.+ T cells were measured. Total cells or CD4.sup.+ cells of draining LN were harvested from each mouse group after CII-immunization and transferred into C57BL/6 mice, and then CIA was induced in recipient mice. The expression levels of ROR[gamma]t and other surface antigens, and the production of cytokines were analyzed in forkhead box P3 (Foxp3).sup.+ regulatory T (Treg) cells. Foxp3.sup.+ Treg cells were analyzed for suppressive activity against proliferation of effector CD4.sup.+ T cells. Interlukin (IL)-10 neutralizing antibody was administrated in the course of CIA. CIA was significantly suppressed in ROR[gamma]t Tg mice compared with C57BL/6 mice. ROR[gamma]t expression and IL-17 production were significantly higher in CII-reactive CD4.sup.+ T cells from ROR[gamma]t Tg mice. Arthritis was significantly attenuated in C57BL/6 mice recipient of cells from ROR[gamma]t Tg mice. Most of Foxp3.sup.+ Treg cells expressed ROR[gamma]t, produced IL-10 but not IL-17, and overexpressed CC chemokine receptor 6 (CCR6) and surface antigens related to the suppressive activity of Foxp3.sup.+ Treg cells in ROR[gamma]t Tg mice. In vitro suppression assay demonstrated significant augmentation of the suppressive capacity of Foxp3.sup.+ Treg cells in ROR[gamma]t Tg mice. CIA was exacerbated in both C57BL/6 mice and ROR[gamma]t Tg mice by the treatment of anti-IL-10 antibody. Our results indicated that ROR[gamma]t overexpression in T cells protected against the development of CIA. The protective effects were mediated, at least in part, through the anti-inflammatory effects including high production of IL-10 of ROR[gamma]t.sup.+Foxp3.sup.+ Treg cells.

Interstitial lung disease (ILD) is induced by various factors in humans. However, the exact mechanism of ILD remains elusive. This study sought to determine the role of natural killer (NK) 1.1+ γδT cells in ILD. The injection of IL-18 plus IL-2 (IL-18/IL-2) into C57BL6 (B6) mice induced acute ILD that resembled early-stage human ILD. An accumulation of NK1.1+ γδT cells similar to NK cells was evident in the lungs. The T Cell Receptor (TCR) Vγ and Vδ repertoires of NK1.1+ γδT cells indicated polyclonal expansion. The expression of IL-2 receptor β (Rβ) and IL-18Rβ in NK1.1+ γδT cells was higher than in NK1.1− γδT cells. IL-18/IL-2 stimulated the proliferation of NK1.1+ γδT cells, but not NK1.1− γδT cells. The IL-18/IL-2–stimulated NK1.1+ γδT cells produced higher concentrations of IFN-γ than did NK1.1− γδT cells. Moreover, NK1.1+ γδT and NK1.1− γδT cells constituted completely different cell populations. The IL-18/IL-2–induced ILD was milder in TCRδ−/− and IFN-γ−/− mice, compared with B6 mice. Furthermore, cell-transfer experiments demonstrated that NK1.1+ γδT cells could induce the expansion of NK cells and IFN-γ mRNA in the lung by IL-18/IL-2. Our results suggest that NK1.1+ γδT cells function as inflammatory mediators in the early phase of IL-18/IL-2–induced ILD.

Invariant natural killer T (iNKT) cells regulate collagen-induced arthritis (CIA) when activated by their potent glycolipid ligand, alpha-galactosylceramide ([alpha]-GalCer). Glucose-6-phosphate isomerase (GPI)-induced arthritis is a closer model of human rheumatoid arthritis based on its association with CD4+ T cells and cytokines such as TNF-[alpha] and IL-6 than CIA. Dominant T cell epitope peptide of GPI (GPI325-339) can induce arthritis similar to GPI-induced arthritis. In this study, we investigated the roles of activation of iNKT cells by [alpha]-GalCer in GPI peptide-induced arthritis. Arthritis was induced in susceptible DBA1 mice with GPI peptide and its severity was assessed clinically. The arthritic mice were treated with either the vehicle (DMSO) or [alpha]-GalCer. iNKT cells were detected in draining lymph nodes (dLNs) by flow cytometry, while serum anti-GPI antibody levels were measured by enzyme-linked immunosorbent assay. To evaluate GPI peptide-specific cytokine production from CD4+ T cells, immunized mice were euthanized and dLN CD4+ cells were re-stimulated by GPI-peptide in the presence of antigen-presenting cells. [alpha]-GalCer induced iNKT cell expansion in dLNs and significantly decreased the severity of GPI peptide-induced arthritis. In [alpha]-GalCer-treated mice, anti-GPI antibody production (total IgG, IgG1, IgG2b) and IL-17, IFN-[gamma], IL-2, and TNF-[alpha] produced by GPI peptide-specific T cells were significantly suppressed at day 10. Moreover, GPI-reactive T cells from mice immunized with GPI and [alpha]-GalCer did not generate any cytokines even when these cells were co-cultured with APC from mice immunized with GPI alone. In vitro depletion of iNKT cells did not alter the suppressive effect of [alpha]-GalCer on CD4+ T cells. [alpha]-GalCer significantly suppressed GPI peptide-induced arthritis through the suppression of GPI-specific CD4+ T cells.

Interstitial lung disease (ILD) is induced by various factors in humans. However, the exact mechanism of ILD remains elusive. This study sought to determine the role of natural killer (NK) 1.1(+) γδT cells in ILD. The injection of IL-18 plus IL-2 (IL-18/IL-2) into C57BL6 (B6) mice induced acute ILD that resembled early-stage human ILD. An accumulation of NK1.1(+) γδT cells similar to NK cells was evident in the lungs. The T Cell Receptor (TCR) Vγ and Vδ repertoires of NK1.1(+) γδT cells indicated polyclonal expansion. The expression of IL-2 receptor β (Rβ) and IL-18Rβ in NK1.1(+) γδT cells was higher than in NK1.1(-) γδT cells. IL-18/IL-2 stimulated the proliferation of NK1.1(+) γδT cells, but not NK1.1(-) γδT cells. The IL-18/IL-2-stimulated NK1.1(+) γδT cells produced higher concentrations of IFN-γ than did NK1.1(-) γδT cells. Moreover, NK1.1(+) γδT and NK1.1(-) γδT cells constituted completely different cell populations. The IL-18/IL-2-induced ILD was milder in TCRδ(-/-) and IFN-γ(-/-) mice, compared with B6 mice. Furthermore, cell-transfer experiments demonstrated that NK1.1(+) γδT cells could induce the expansion of NK cells and IFN-γ mRNA in the lung by IL-18/IL-2. Our results suggest that NK1.1(+) γδT cells function as inflammatory mediators in the early phase of IL-18/IL-2-induced ILD.