PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

The interferon regulatory factors, a double-edged sword, in the pathogenesis of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease resulted from the unrestrained inflammatory attack towards the insulin-producing islet ß cells. Although the exact etiology underlying T1D remains elusive, viral infections, especially those specific strains of enterovirus, are acknowledged as a critical environmental cue involved in the early phase of disease initiation. Viral infections could either directly impede ß cell function, or elicit pathological autoinflammatory reactions for ß cell killing. Autoimmune responses are bolstered by a massive body of virus-derived exogenous pathogen-associated molecular patterns (PAMPs) and the presence of ß cell-derived damage-associated molecular patterns (DAMPs). In particular, the nucleic acid components and the downstream nucleic acid sensing pathways serve as the major effector mechanism. The endogenous retroviral RNA, mitochondrial DNA (mtDNA) and genomic fragments generated by stressed or dying ß cells induce host responses reminiscent of viral infection, a phenomenon termed as viral mimicry during the early stage of T1D development. Given that the interferon regulatory factors (IRFs) are considered as hub transcription factors to modulate immune responses relevant to viral infection, we thus sought to summarize the critical role of IRFs in T1D pathogenesis. We discuss with focus for the impact of IRFs on the sensitivity of ß cells to cytokine stimulation, the vulnerability of ß cells to viral infection/mimicry, and the intensity of immune response. Together, targeting certain IRF members, alone or together with other therapeutics, could be a promising strategy against T1D.

The role of hydrogen sulphide signalling in macrophage activation.

Hydrogen sulphide (H2 S) is the latest identified small gaseous mediator enabled by its lipophilic nature to freely permeate the biological membranes. Initially, H2 S was recognized by its roles in neuronal activity and vascular relaxation, which makes it an important molecule involved in paracrine signalling pathways. Recently, the immune regulatory function of gasotransmitters, H2 S in particular, is increasingly being appreciated. Endogenous H2 S level has been linked to macrophage activation, polarization and inflammasome formation. Mechanistically, H2 S-induced protein S-sulphydration suppresses several inflammatory pathways including NF-κB and JNK signalling. Moreover, H2 S serves as a potent cellular redox regulator to modulate epigenetic alterations and to promote mitochondrial biogenesis in macrophages. Here in this review, we intend to summarize the recent advancements of H2 S studies in macrophages, and to discuss with focus on the therapeutic potential of H2 S donors by targeting macrophages. The feasibility of H2 S signalling component as a macrophage biomarker under disease conditions would be also discussed.

GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis.

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.

Comparative analysis of pre- and postmenopausal endometrial cancer in 216 patients.

Background: Endometrial carcinoma (EC) is one of the most common gynecological malignancies and has become more prevalent in recent decades. The clinical manifestations and characteristics of EC in premenopausal and postmenopausal women differ and present with distinct pathological stages and subtypes of EC. Surgery remains the principal therapeutic approach, but the postoperative prognosis is largely affected by the pathological state. Methods: A retrospective study was conducted on 216 patients with EC who were hospitalized from August 2008 to August 2019 in Wuhan Union Hospital. The patients were divided into 2 groups based on the pre- or postmenopausal occurrence of EC. The general clinical characteristics, intraoperative situation, clinicopathological data, and postoperative outcomes of the 2 groups were compared. Results: Patients with premenopausal EC had earlier menarche, a higher incidence of primary infertility and anemia, and fewer pregnancies and deliveries. Patients with postmenopausal EC were older and often had hyperlipidemia and diabetes. Additionally, patients who were postmenopausal had worse tumor pathological gradings, more severe muscular invasion, and a higher rate of lymphatic metastasis. These factors led to a higher demand for postoperative radiotherapy in patients but a lower survival rate. Conclusions: Generally, premenopausal EC differs from postmenopausal EC: the latter is more malignant and has a worse prognosis.

Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.

Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained ß cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory ß cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy.

UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer.

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

The Essential Role of FoxO1 in the Regulation of Macrophage Function.

Macrophages are widely distributed in various tissues and organs. They not only participate in the regulation of innate and adaptive immune response, but also play an important role in tissue homeostasis. Dysregulation of macrophage function is closely related to the initiation, development and prognosis of multiple diseases, including infection and tumorigenesis. Forkhead box transcription factor O1 (FoxO1) is an important member among the forkhead box transcription factor family. Through directly binding to the promoter regions of downstream target genes, FoxO1 is implicated in cell proliferation, apoptosis, metabolic activities and other biological processes. In this review, we summarized the regulatory role of FoxO1 in macrophage phagocytosis, migration, differentiation and inflammatory activation. We also emphasized that macrophage reciprocally modulated FoxO1 activity via a post-translational modification (PTM) dominant manner.

Aloperine Ameliorates IMQ-Induced Psoriasis by Attenuating Th17 Differentiation and Facilitating Their Conversion to Treg.

Aloperine is an anti-inflammatory compound isolated from the Chinese herb Sophora alopecuroides L. Previously, our group has reported that the generation of induced Treg was promoted by aloperine treatment in a mouse colitis model. However, the effect of aloperine on effector T cell subsets remains unclear. We therefore carefully examined the effect of aloperine on the differentiation of major subsets of T helper cells. Based on our results, psoriasis, a Th17 dominant skin disease, is selected to explore the potential therapeutic effect of aloperine in vivo. Herein, we demonstrated that topical application of aloperine suppressed epidermal proliferation, erythema, and infiltration of inflammatory cells in skin lesions. Mechanistic studies revealed that aloperine suppressed the differentiation of Th17 cells directly through inhibiting the phosphorylation of STAT3 or indirectly through impairing the secretion of Th17-promoting cytokines by dendritic cells. Moreover, aloperine enhanced the conversion of Th17 into Treg via altering the pSTAT3/pSTAT5 ratio. Collectively, our study supported that aloperine possesses the capacity to affect Th17 differentiation and modulates Th17/Treg balance, thereby alleviating imiquimod (IMQ)-induced psoriasis in mice.

SUMOylation of PDPK1 Is required to maintain glycolysis-dependent CD4 T-cell homeostasis.

The immune system is finely tuned to fight against infections, eradicate neoplasms, and prevent autoimmunity. Protein posttranslational modification (PTM) constitutes a molecular layer of regulation to guarantee the proper intensity of immune response. Herein, we report that UBC9-mediated protein SUMOylation plays an essential role in peripheral CD4 T-cell proliferation, but without a perceptible impact on T-cell polarization. Both conventional T-cell (Tcon) and regulatory T-cell (Treg) maintenance are differentially affected, which was likely caused by a shared deficit in cell glycolytic metabolism. Mechanistically, PDPK1 (3-phosphoinositide-dependent protein-kinase 1) was identified as a novel SUMOylation substrate, which occurred predominantly at lysine 299 (K299) located within the protein-kinase domain. Loss of PDPK1 SUMOylation impeded its autophosphorylation at serine 241 (S241), thereby leading to hypoactivation of downstream mTORC1 signaling coupled with incompetence of cell proliferation. Altogether, our results revealed a novel regulatory mechanism in peripheral CD4 T-cell homeostatic proliferation, which involves SUMOylation regulation of PDPK1-mTORC1 signaling-mediated glycolytic process.

High thermal durability of Ru-based synthetic antiferromagnet by interfacial engineering with Re insertion.

Synthetic antiferromagnets (SAFs), composed of Ru spacer with a Re insertion layer, reveal superior thermal stability up to 450 °C annealing, making the back-end of line process a wider manufacturing window and tolerance to integrate the perpendicular magnetic tunneling junctions (P-MTJs) into CMOS process. The coupling strength decays significantly for SAFs with single Ru spacer after annealing above 400 °C. Due to the characteristics of refractory metals, Re can behave as a diffusion barrier during annealing. Furthermore, the Re spacer can still keep reasonable RKKY coupling strength. Therefore, the SAFs with Ru/Re composite spacers exhibit higher RKKY coupling strength than Ru spacers after 450 °C annealing. In addition, we discovered the different enhancements for the upper and lower interfacial Re insertion, which was attributed to the varied defect formation at interfaces. The stacking fault was formed at the upper Ru/Co interface in as-deposited state. When Re was inserted at the upper interface, the diffusion between Co and Ru was significantly suppressed and the stacking fault can be eliminated during annealing, leading to enhanced interlayer coupling. Through the interfacial engineering, we may have more degrees of freedom to tune the SAF performance and thus enhance process compatibility of P-MTJ to the CMOS process.

Revisiting the Antigen-Presenting Function of ß Cells in T1D Pathogenesis.

Type 1 diabetes (T1D) is characterized by the unresolved autoimmune inflammation and islet ß cell destruction. The islet resident antigen-presenting cells (APCs) including dendritic cells and macrophages uptake and process the ß cell-derived antigens to prime the autoreactive diabetogenic T cells. Upon activation, those autoreactive T cells produce copious amount of IFN-γ, TNF-α and IL-1ß to induce ß cell stress and death. Autoimmune attack and ß cell damage intertwine together to push forward this self-destructive program, leading to T1D onset. However, ß cells are far beyond a passive participant during the course of T1D development. Herein in this review, we summarized how ß cells are actively involved in the initiation of autoimmune responses in T1D setting. Specifically, ß cells produce modified neoantigens under stressed condition, which is coupled with upregulated expression of MHC I/II and co-stimulatory molecules as well as other immune modules, that are essential properties normally exhibited by the professional APCs. At the cellular level, this subset of APC-like ß cells dynamically interacts with plasmacytoid dendritic cells (pDCs) and manifests potency to activate autoreactive CD4 and CD8 T cells, by which ß cells initiate early autoimmune responses predisposing to T1D development. Overall, the antigen-presenting function of ß cells helps to explain the tissue specificity of T1D and highlights the active roles of structural cells played in the pathogenesis of various immune related disorders.

The MAPK dual specific phosphatase (DUSP) proteins: A versatile wrestler in T cell functionality.

The functional state of T cells is diverse and under dynamic control for adapting to the changes of microenvironment. Reversible protein phosphorylation represents an important post-translational modification that not only involves in the immediate early response of T cells, but also affects their functionality in the long run. Perturbation of global phosphorylation profile and/or phosphorylation of specific signaling nodes result in aberrant T cell activity. Dual specific phosphatases (DUSPs), which target MAPKs and beyond, have increasingly been emerged as a versatile regulator in T cell biology. Herein in this mini review, we sought to summarize and discuss the impact of DUSP proteins on the regulation of effector T cell activity, T cell polarization, regulatory T cell development and T cell senescence/exhaustion. Given the distinctive engagement of each DUSP member under various disease settings such as chronic infection, autoimmune disorders, cancer and age-related diseases, DUSP proteins likely hold the promise to become a druggable target other than the existing therapeutics that are predominantly by manipulating protein kinase activity.

GEO data mining and TCGA analysis reveal altered branched chain amino acid metabolism in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor of the digestive system which has a less than 1% 5-year survival rate. The pathogenesis of PDAC development is incompletely understood. Genetic predisposition, disease history of chronic pancreatitis and diabetes elevate the risk of PDAC while environmental and dietary factors including smoking, alcohol abuse, high fat/protein intake as well as air pollution exacerbate PDAC progression. BCAAs, consisting of leucine, isoleucine and valine are essential amino acids that are obtained from food and play versatile roles in carcinogenesis. Recent studies have demonstrated that BCAA metabolism affects PDAC development but the results are controversial. To explore the possible engagement of BCAA metabolism in PDAC, we took advantage of the GEO and TCGA database and discovered that BCAA uptake is closely related to PDAC development while BCAA catabolism is down-regulated in PDAC tissue. Besides, NOTCH and MYC are differentially involved in BCAA metabolism in tumor and muscle, and enhanced lipid synthesis is independent of BCAA catabolism. Altogether, we highlight BCAA uptake as a promising target for PDAC treatment.

Scalable Epitaxial Growth of WSe2 Thin Films on SiO2/Si via a Self-Assembled PtSe2 Buffer Layer.

The growth of large-area epitaxial transition metal dichalgogenides (TMDCs) are of central importance for scalable integrated device applications. Different methods have been developed to achieve large-sized high quality films. However, reliable approaches for centimeter-sized or even wafer-level epitaxial growth of TMDCs are still lacking. Here we demonstrate a new method to grow inch-sized epitaxial WSe2 films on SiO2/Si substrates at a much lower temperature with high repeatability and scalability. High quality crystalline films are achieved through direct selenization of a tungsten film with platinum as the underlayer. The self-assembled PtSe2 buffer layer, formed during selenization, assists epitaxial growth of WSe2. Using fabricated WSe2 films, excellent performance memory devices are demonstrated. As a member of the TMDC family, our findings based on WSe2 may also be applied to other TMDC materials for large-scale production of high quality TMDC films for various applications.

Wavelength control of tunable dense wavelength-division multiplexing sources by use of a Fabry-Perot etalon and a semiconductor optoelectronic diode.

A high-resolution tunable-wavelength controller is achieved by use of an etalon for control of wavelength drift and a semiconductor optical diode (SOD) for channel recognition. The etalon provides a stable wavelength reference, and the SOD can detect mode-hopping and incomplete-tuning problems in tuning a laser. With the help of a Fabry-Perot etalon as a precise wavelength reference, the usual concern with the temperature stability of a SOD can be relaxed at least tenfold compared with wavelength control with a single SOD. We demonstrate the feasibility of monitoring tunable lasers by using a Fabry-Perot laser diode (FPLD) or a semiconductor optical amplifier (SOA). The induced voltage of the FPLD and that of the SOA are modeled with analytic expressions that can help to optimize the operation of a SOD sensor.