Co-inhibitory receptors (IRs) are molecules that protect host against autoimmune reactions and maintain peripheral self-tolerance, playing an essential role in maintaining immune homeostasis. In view of the substantial clinical progresses of negative immune checkpoint blockade in cancer treatment, the role of IRs in autoimmune diseases is also obvious. Several advances highlighted the substantial impacts of T cell immunoglobulin and ITIM domain (TIGIT), a novel IR, in autoimmunity. Blockade of TIGIT pathway exacerbates multiple autoimmune diseases, whereas enhancement of TIGIT function has been shown to alleviate autoimmune settings in mice. These data suggested that TIGIT pathway can be manipulated to achieve durable tolerance to treat autoimmune disorders. In this review, we provide an overview of characteristics of TIGIT and its role in autoimmunity. We then discuss recent approaches and future directions to leverage our knowledge of TIGIT as therapeutic target in autoimmune diseases.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is still a major cause of the morbidity and mortality of SLE. In clinical practice, diagnosis, and therapy of SLE is complicated and challenging due to lack of ideal biomarkers. Exosomes could be detected from numerous kinds of biological fluids and their specific contents are considered as hallmarks of autoimmune diseases. The exosomal miRNA profiles of SLE/LN patients significantly differ from those of the healthy controls making them as attractive biomarkers for renal injury. Exosomes are considered as optimal delivery vehicles owing to their higher stable, minimal toxicity, lower immunogenicity features and specific target effects. Endogenous miRNAs can be functionally transferred by exosomes from donor cells to recipient cells, displaying their immunomodulatory effects. In addition, it has been confirmed that exosomal miRNAs could directly interact with Toll-like receptors (TLRs) signaling pathways to regulate NF-κB activation and the secretion of inflammatory cytokines. The present Review mainly focuses on the immunomodulatory effects of exosomal-miRNAs, the complex interplay between exosomes, miRNAs and TLR signaling pathways, and how the exosomal-miRNAs can become non-invasive diagnostic molecules and potential therapeutic strategies for the management of SLE.

Triggering receptors expressed on myeloid cell-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). In this study, we screen TREM-1 as one of the hub genes closely correlated with the progression of SLE and identify soluble TREM-1 (sTREM-1) in serum as a valuable diagnostic biomarker for SLE.Moreover, activation of TREM-1 by its agonist promotes activation and chemotaxis of mDCs and increases production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α and MCP-1. Disorders of epigenetic processes including non-coding RNA give rise to SLE, resulting in complicated syndromes. Herein, we show that lupus mice display a unique miRNA signature in spleen, among which miR-150 is the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppresses the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicates that administration of miR-150-5p agomir effectively ameliorates lupus symptoms. Intriguingly, miR-150 inhibits the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues. Overall, TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.

Backgroud: Increasing evidences suggest that the dysregulation of iron metabolism is linked to the onset and progression of breast cancer. However, prognostic value and therapeutic importance of iron metabolism-related genes in breast cancer remain unclear. Methods RNA sequencing information, clinicopathological data, and iron metabolism-related gene sets were obtained from The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database and the Molecular Signatures Database. The risk score model was constructed and validated using GSEA, univariate, multivariate Cox, and LASSO regression analysis. The tumor microenvironment landscape of risk model was then evaluated. Finally, we predicted the immunotherapy response and drug prediction of iron metabolism-related signature. Results A total of 7 iron metabolism-related genes were identified, and a novel risk signature was developed in the training cohort for prognosis and risk stratification. The prognostic value of this model was also verified in the testing cohort. Moreover, a nomogram model was constructed and shown high predictive accuracy for 1-, 3-, and 5-year OS rate estimates. In addition, the high risk group had significantly higher immune, stromal and estimate scores, increased immunosuppressive cell infiltrations, elevated marker genes of cancer associated fibroblasts, lower tumor mutation burden, and worse response to anti-PD-L1 immunotherapy. Finally, the associations between drug sensitivity and risk model were analyzed, which might explore targeted drugs to improve the clinical outcomes for breast cancer patients. Conclusions The iron metabolism-related gene prognostic signature was developed and validated, which might provide a method for predicting the prognosis and survival of breast patients, as well as potential targets and drugs for immunotherapy.

Triggering receptors expressed on myeloid cell-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). In this study, we screen TREM-1 as one of the hub genes closely correlated with the progression of SLE and identify soluble TREM-1 (sTREM-1) in serum as a valuable diagnostic biomarker for SLE. Moreover, activation of TREM-1 by its agonist promotes activation and chemotaxis of mDCs and increases production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α and MCP-1. Disorders of epigenetic processes including non-coding RNA give rise to SLE, resulting in complicated syndromes. Herein, we show that lupus mice display a unique miRNA signature in spleen, among which miR-150 is the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppresses the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicates that administration of miR-150-5p agomir effectively ameliorates lupus symptoms. Intriguingly, miR-150 inhibits the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues. Overall, TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.