In rheumatoid arthritis (RA), imbalanced T cells subsets play a critical role in sustaining chronic inflammatory responses in the synovium. Naïve T cells in RA patients undergo maldifferentiation, including an increase in the effector Th1/Th17 lineage and a reduction in regulatory T (Treg) cells. Upon stimulation, naïve CD4+CD45RO- T cells from RA patients exhibited insufficient expression of Foxp3, which induced a deficiency in Tregs production and an imbalance of Treg/Th17 differentiation. Further mechanistic study indicated that RA T cells failed to produce sufficient levels of the histone acetyltransferase Tip60, leading to reduced acetylation of Foxp3; this, in turn, decreased Foxp3 expression, impaired Treg commitment, and promoted Th17 production. Moreover, in human synovium chimeric mice, suppression of Tip60 activity in healthy T cells promoted tissue infiltration and arthritogenesis, while reconstitution of Tip60 in RA T cells suppressed synovitis and effector T cell infiltration. Our findings link T cell maldifferentiation and tissue infiltration with Tip60-mediated Foxp3 acetylation and identify Tip60 as a potential therapeutic target for suppression of tissue inflammation and autoimmunogenesis in RA.

Rheumatoid arthritis (RA) is an autoimmune-mediated disease that is associated with significant cartilage damage and immunosenescence. Despite decades of research, the major signal pathways that initiate RA are still unclear. The DNA damage response (DDR) is a specific and hierarchical network that includes cell cycle checkpoints, DNA repair, and DNA-damage tolerance pathways. Recent studies suggest that this condition is associated with deficits in telomere maintenance and overall genomic instability in the T cells of RA patients. Analysis of the underlying mechanisms has revealed defects in DDR pathways. Particularly, the DNA repair enzyme, ataxia telangiectasia mutated (ATM), is downregulated, which leaves the damaged DNA breaks in RA-associated T cells unrepaired and pushes them to apoptosis, exhausts the T cell pool, and promotes the arthritogenesis effector function of T cells. This review discusses recent advancements and illustrates that risk factors for RA, such as viral infections, environmental events, and genetic risk loci are combat with DDR signals, and the impaired DDR response of RA-associated T cells, in turn, triggers disease-related phenotypes. Therefore, DDR is the dominant signal that converts genetic and environmental stress to RA-related immune dysfunction. Understanding the orchestration of RA pathogenesis by DDR signals would further our current knowledge of RA and provide novel avenues in RA therapy.

Background: The efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate cancer. The ataxia telangiectasia mutation (ATM) protein plays a crucial role in maintaining genome stability and function of mitosis. Here, we aimed to determine whether PD-1/PD-L1 signaling contributes to the resistance to DTX and to elucidate the mechanism underlying DTX-induced PD-L1 expression. Methods: In this retrospective study, PD-L1 expression was analyzed in 33 tumor tissue samples from prostate cancer patients. Prostate cell lines were used to perform functional assays and examine underlying mechanisms in vitro. A fully mouse prostate cancer model and a humanized chimeric mouse bearing human prostate tumors and peripheral blood mononuclear cells were used for in vivo assays. Results: We have shown that DTX, a chemotherapeutic drug which causing microtubule interference, could significantly induce the expression of PD-L1 in prostate cancer cells. This effect is blocked by the inhibition of ATM, suggesting that it plays an essential role in PD-L1 expression upregulated by DTX. Mechanistic studies have shown that ATM activity in cancer cells enhances the stability of the NF-κB essential modulator (NEMO), which leading to an increase in the NF-κB activity and PD-L1 expression. Using the mouse model, it was further demonstrated that a combination of ATM and NEMO inhibitors along with DTX augmented the antitumor efficacy of chemotherapy, which are comparable to that of PD-L1 antibody. Conclusions: Our findings have revealed that a previously unrecognized ATM-NEMO signaling which induced by DTX is capable of suppressing tumor immunity by activating the expression of PD-L1, suggesting that the ATM-NEMO-NF-κB axis can be exploited to restore the immune balance and overcome cancer resistance triggered by DTX. Graphic Abstract: supplementary file 1

Objective: Activation of osteoclastogenesis at the bone site in rheumatoid arthritis (RA) is well established. The mechanisms by which circulating osteoclast precursors contribute are still unclear. Peroxisome proliferator–activated receptor γ coactivator 1β (PGC‐1β) is implicated in transcriptional regulation of osteoclastogenesis in mouse models. This study was undertaken to investigate the contribution of PGC‐1β to circulating osteoclast precursors and its link to bone destruction in RA.Methods: PGC‐1β expression in RA peripheral blood CD14+ monocytes was increased and showed correlation with joint destruction shown on radiographs. Cells from RA patients or healthy controls were transfected with a lentivirus vector for PGC‐1β gene silencing or overexpression and cultured with macrophage colony‐stimulating factor and RANKL. Bone resorption activity, bone‐degrading enzymes, and signaling molecules were measured in these mature osteoclasts.Results: Increased nuclear accumulation of PGC‐1β was observed in RA peripheral blood CD14+ monocytes, and these cells had stronger osteoclastogenesis than in healthy controls. PGC‐1β protein expression was positively correlated with radiographic joint destruction (r = 0.396–0.413; all P < 0.05). PGC‐1β knockdown suppressed (51–82% reduction) the expression of cathepsin K, tartrate‐resistant acid phosphatase (TRAP), and matrix metalloproteinase 9 (MMP‐9), as well as osteoclast differentiation and bone resorption activity. Conversely, PGC‐1β overexpression increased these markers (by 1.5–1.8‐fold) and osteoclastogenesis. VIVIT, an inhibitor of NFATc1 activation, inhibited the effect of overexpressed PGC‐1β by reducing cathepsin K, TRAP, and MMP‐9 expression. Chromatin immunoprecipitation assay and dual‐luciferase reporter gene assay showed PGC‐1β bound to NFATc1 promoter, leading to transcriptional activation.Conclusion: Activation of the PGC‐1β/NFATc1 pathway in circulating osteoclast precursors was associated with bone destruction in RA. This may represent a new treatment target.

The overproduction of osteoclasts, leading to bone destruction in patients with rheumatoid arthritis (RA), is well established. However, little is known about the metabolic dysfunction of osteoclast precursors (OCPs) in RA. Herein, we show that increasing fatty acid oxidation (FAO) induces OCP fusion. Carnitine palmitoyltransferase IA (CPT1A), which is important for carnitine transportation and is involved in FAO in the mitochondria, is upregulated in RA patients. This metabolic change further increases the expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) by enhancing the binding of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) to the promoters of CLTA and CLTC. This drives clathrin-dependent endocytosis pathway, which attenuates fusion receptors in the cellular membrane and contributes to increased podosome structure formation. This study reveals a new mechanism through which FAO metabolism participates in joint destruction in RA and provides a novel therapeutic direction for the development of drugs against bone destruction in patients with RA.

Immunotherapy for prostate cancer (PCa) faces serious challenges. Therefore, the co-inhibitory receptors that regulate T cell function of PCa must be elucidated. Here we identified that the inhibitory receptor LAG3 was significantly induced in T cells from PCa patients. Gene array analysis revealed that insufficient ataxia telangiectasia mutated (ATM) gene expression in PCa T cells was responsible for the elevated LAG3 expression. Mechanistically, insufficient ATM expression impaired its ability to activate AMPKα signaling and CD4⁺ T cell functions, which further enhances the binding of the transcription factors XBP1 and EGR2 to LAG3 promoter. Reconstitution of ATM and inhibition of XBP1 or EGR2 in PCa T cells suppressed LAG3 expression and restored the effector function of CD4⁺ T cells from PCa. Our study revealed the mechanism of LAG3 upregulation in CD4⁺ T lymphocytes of PCa patients and may provide insights for the development of immunotherapeutic strategies for PCa treatment.