Objective. Neutrophil extracellular traps (NETs) have been shown to play an important role in systemic lupus erythematosus (SLE) pathogenesis by activating plasmacytoid dendritic cells (PDCs) and the type I interferon (IFN) pathway. NETs composed of self-DNA are considered to be of nuclear origin and are a major source of anti-DNA autoantibody generation. This study was undertaken to evaluate whether mitochondrial DNA (mtDNA) resides in NETs, to evaluate whether mtDNA and antimtDNA antibodies cause dysregulation of the PDC-IFNa pathway, and to investigate the clinical implication in SLE.Methods. Patients with SLE (n 5 102), patients with rheumatoid arthritis (n 5 30), and healthy donors (n 5 40) were enrolled in in vitro studies. NETs were generated from phorbol 12-myristate 13-acetate (PMA)-stimulated peripheral neutrophils. Immunofluorescence staining was used to detect NET formation ex vivo and in lupus nephritis renal biopsy samples. The mtDNA levels and type I IFN-inducible gene scores were measured by quantitative polymerase chain reaction. Anti-mtDNA antibodies, anti-double-stranded DNA (anti-dsDNA) antibodies, and IFNa were detected by enzyme-linked immunosorbent assay. Purified PDCs were stimulated by isolated NETs, mtDNA, or dsDNA, combined with anti-mtDNA or dsDNA IgG, or other culture conditions. Additional patients with SLE (n 5 113) were enrolled in a proof-ofconcept trial. We evaluated the efficacy and safety of metformin on a background of corticosteroids and conventional immunosuppressive agents in patients with mild or moderate lupus. The primary end point was the efficacy of metformin for reducing disease flare.Results. We detected mtDNA in NETs, and antimtDNA antibody levels were elevated in SLE patients compared with controls and significantly correlated with IFN scores and the disease activity index. The presence of anti-mtDNA antibodies was disproportionately associated with lupus nephritis, and correlated better than anti-dsDNA antibody levels with the lupus nephritis activity index. Mitochondrial DNA was deposited in NETs in lupus nephritis renal biopsy specimens. In addition, mtDNA/anti-mtDNA were greater inducers of PDC IFNa production via Toll-like receptor engagement than dsDNA/anti-dsDNA. We assessed the effect of metformin on down-regulating the NET mtDNA-PDC-IFNa pathway. Metformin decreased PMA-induced NET formation and CpG-stimulated PDC IFNa generation. A proof-ofconcept trial of metformin add-on treatment of mild or moderate SLE resulted in decreases in clinical flares, prednisone exposure, and body weight.Conclusion. Our findings establish a link between mtDNA in NETs, anti-mtDNA antibodies, and PDC IFNa pathogenesis in SLE, and highlight that specific strategies to down-regulate this pathway, such as treatment with metformin, may be new approaches to treat SLE.The type I interferon (IFN) pathway plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). It is well known that self-DNA and other nuclear antigens, along with their autoantibodies, are potent...

Reduced food intake is common to many pathological conditions, such as infection and toxin exposure. However, cortical circuits that mediate feeding responses to these threats are less investigated. The anterior insular cortex (aIC) is a core region that integrates interoceptive states and emotional awareness and consequently guides behavioral responses. Here, we demonstrate that the right-side aIC CamKII+ (aICCamKII) neurons in mice are activated by aversive visceral signals. Hyperactivation of the right-side aICCamKII neurons attenuates food consumption, while inhibition of these neurons increases feeding and reverses aversive stimuli-induced anorexia and weight loss. Similar manipulation at the left-side aIC does not cause significant behavioral changes. Furthermore, virus tracing reveals that aICCamKII neurons project directly to the vGluT2+ neurons in the lateral hypothalamus (LH), and the right-side aICCamKII-to-LH pathway mediates feeding suppression. Our studies uncover a circuit from the cortex to the hypothalamus that senses aversive visceral signals and controls feeding behavior.

ObjectiveTo evaluate the risk of major infections and the relationship between major infections and mortality in patients with newly diagnosed SLE.MethodsA newly diagnosed (<3 months) hospitalised Systemic Lupus Inception Cohort (hSLIC) in our centre during 1 January 2013 and 1 November 2020 was established. All patients were followed up for at least 1 year or until death. Patient baseline characteristics were collected. Major infection events were recorded during follow-up, which were defined as microbiological/clinical-based diagnosis treated with intravenous antimicrobials. The cohort was further divided into a training set and a testing set. Independent predictors of major infections were identified using multivariable logistic regression analysis. Kaplan-Meier survival analyses were conducted.ResultsAmong the 494 patients enrolled in the hSLIC cohort, there were 69 documented episodes of major infections during the first year of follow-up in 67 (14%) patients. The major infection events predominantly occurred within the first 4 months since enrolment (94%, 65/69) and were associated with all-cause mortality. After adjustments for glucocorticoid and immunosuppressant exposure, a prediction model based on SLE Disease Activity Index >10, peripheral lymphocyte count <0.8×109/L and serum creatinine >104 µmol/L was established to identify patients at low risk (3%–5%) or high risk (37%–39%) of major infections within the first 4 months.ConclusionsNewly onset active SLE is susceptible to major infections, which is probably due to underlying profound immune disturbance. Identifying high-risk patients using an appropriate prediction tool might lead to better tailored management and better outcome.