TLR7 activation by imiquimod worsens glycemic control in female FVB/N mice consuming a high-fat diet.

Toll-like receptor-7 (TLR7) activation promotes autoimmunity, and metabolic syndrome (MetS) is a common comorbidity in patients with autoimmune disease. We previously demonstrated hyperinsulinemia in TLR7 agonist imiquimod (IMQ)-treated, high-fat diet (HFD)-fed female C57BL/6 mice. Since mouse strains differ in susceptibility to MetS and target organ damage, this study investigated whether 12 weeks of exposure to HFD and IMQ promoted MetS, autoimmunity, and target organ damage in female FVB/N mice. Supporting early-stage autoimmunity, spleen-to-tibia ratio, and anti-nuclear antibodies (ANA) were significantly increased by IMQ. No significant effect of IMQ on urinary albumin excretion or left ventricular hypertrophy was observed. HFD increased liver-to-tibia ratio, which was further exacerbated by IMQ. HFD increased fasting blood glucose levels at the end of 12 weeks, but there was no significant effect of IMQ treatment on fasting blood glucose levels at 6 or 12 weeks of treatment. However, oral glucose tolerance testing at 12 weeks revealed impaired glucose tolerance in HFD-fed mice compared to control diet mice together with IMQ treatment exacerbating the impairment. Accordingly, these data suggest TLR7 activation also exacerbates HFD-induced dysregulation of glucose handling FVB/N mice, supporting the possibility that endogenous TLR7 activation may contribute to dysglycemia in patients with autoimmune disease.

Development of High Fat Diet-Induced Hyperinsulinemia in Mice Is Enhanced by Co-treatment With a TLR7 Agonist.

Metabolic syndrome (MetS) is common in Systemic Lupus Erythematosus (SLE) patients and is associated with increased cardio-renal risk. Toll-like receptor 7 (TLR7) stimulation promotes the development of SLE through mechanisms including activating type I Interferon (IFN) and autoreactive B cells. The current study tested whether combined TLR7 agonist treatment and exposure to a high fat, high sucrose "Western diet" intervention affects the early-stage development of SLE or MetS features. Female C57BL/6 mice were untreated or treated with the TLR7 agonist imiquimod (IMQ) and fed a high-fat diet (HFD; fat 42% kcal, sucrose 34% kcal) or control diet (fat 12.6% kcal, sucrose 34% kcal) for 6 weeks. Supporting early-stage induction of autoimmunity, spleen weights were significantly increased and anti-nuclear antibody (ANA) positivity was detected in IMQ-treated mice. Increased body weight, gonadal fat pad mass, and plasma leptin levels were observed between HFD and control animals for both IMQ and untreated mice. However, the increase in these parameters with HFD was slightly but significantly diminished in IMQ-treated mice. Both the HFD and IMQ treatments significantly increased fasting blood glucose levels. Notably, IMQ treatment affected fasting insulin concentrations in a diet-dependent manner, with hyperinsulinemia observed in IMQ-HFD treated mice. Together, this indicates that the IMQ model of SLE is associated with metabolic alterations, impaired glycemic control, and hyperinsulinemia under HFD conditions. This model may be helpful in further investigating the relationship between MetS and SLE, and supports a role of TLR7 signaling in promoting or accelerating the development of dysglycemia and hyperinsulinemia.

Autoimmune-mediated renal disease and hypertension.

Hypertension is a major risk factor for cardiovascular disease, chronic kidney disease (CKD), and mortality. Troublingly, hypertension is highly prevalent in patients with autoimmune renal disease and hastens renal functional decline. Although progress has been made over the past two decades in understanding the inflammatory contributions to essential hypertension more broadly, the mechanisms active in autoimmune-mediated renal diseases remain grossly understudied. This Review provides an overview of the pathogenesis of each of the major autoimmune diseases affecting the kidney that are associated with hypertension, and describes the current state of knowledge regarding hypertension in these diseases and their management. Specifically, discussion focuses on Systemic Lupus Erythematosus (SLE) and Lupus Nephritis (LN), Immunoglobulin A (IgA) Nephropathy, Idiopathic Membranous Nephropathy (IMN), Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated glomerulonephritis, and Thrombotic Thrombocytopenic Purpura (TTP). A summary of disease-specific animal models found to exhibit hypertension is also included to highlight opportunities for much needed further investigation of underlying mechanisms and novel therapeutic approaches.

Erythropoietin protects polychlorinated biphenyl (Aroclor 1254) induced neurotoxicity in mice.

Erythropoietin is a hematopoietic cytokine factor with various biological effects and its receptors are expressed in the central nervous system, which helps in normal brain development and exerts neuroprotection in different models of brain injury. The present study was designed to evaluate the neuroprotective role of erythropoietin in Aroclor 1254 induced oxidative stress in mice. Neurotoxicity was induced by Aroclor 1254 (10 mg/kg bw/day). Erythropoietin was administered simultaneously with Aroclor 1254 for 14 days in co-treatment groups and administered before induction of neurotoxicity for 7 days in case of pretreatment groups. To assess the behavioural parameters in observation with learning and memory, open field and Y-maze were employed. Acetylcholinesterase, glutamate, antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase) were estimated in brain tissue and corticosterone in plasma to evaluate the intensity of oxidative signalling in brain. Triglycerides and total cholesterol were estimated in plasma. Both doses of erythropoietin (500 and 1000 IU/kg) pretreatment and co-treatment, (i) significantly increased the habituation memory and percentage alteration which are indicative of the cognitive improvement, (ii) attenuated the Aroclor 1254 induced rise in acetylcholinesterase activity, corticosterone, triglycerides and total cholesterol, (iii) increased the glutamate and antioxidant enzyme levels. These results indicate that erythropoietin protects against Aroclor 1254 induced neurotoxicity and improves the cognitive function and that this cytokine could be a promising therapeutic agent for stress induced neurodegeneration.