Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year. We identified a feedforward loop of microglial activation and microglia-dependent synapse elimination dependent on neuronal secretion of high mobility group box 1 protein (HMGB1) which binds the receptor for advanced glycation end products (RAGE) and leads to microglial secretion of C1q, upregulation of interleukin-10 with consequent downregulation of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), an inhibitory receptor for C1q. Treatment with a centrally acting angiotensin-converting enzyme inhibitor or with an angiotensin-receptor blocker restored a healthy equilibrium, microglial quiescence and intact spatial memory.

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross- reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus1. This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory. Both microglia and C1q are required for dendritic loss1. Here we show that this pattern of hippocampal injury creates a maladaptive equilibrium that is sustained for at least one year. It requires HMGB1 secretion by neurons to bind RAGE, a receptor for HMGB1 expressed on microglia, and leads to decreased expression of microglial LAIR-1, an inhibitory receptor for C1q. The angiotensin converting enzyme (ACE) inhibitor captopril, which can restore a healthy equilibrium, microglial quiescence, and intact spatial memory, leads to upregulation of LAIR-1. This paradigm highlights HMGB1:RAGE and C1q:LAIR-1 interactions as pivotal pathways in the microglial-neuronal interplay that defines a physiologic versus a maladaptive equilibrium.

Cognitive Impairment in SLE: Mechanisms and Therapeutic Approaches.

A wide range of patients with systemic lupus erythematosus (SLE) suffer from cognitive dysfunction (CD) which severely impacts their quality of life. However, CD remains underdiagnosed and poorly understood. Here, we discuss current findings in patients and in animal models. Strong evidence suggests that CD pathogenesis involves known mechanisms of tissue injury in SLE. These mechanisms recruit brain resident cells, in particular microglia, into the pathological process. While systemic immune activation is critical to central nervous system injury, the current focus of therapy is the microglial cell and not the systemic immune perturbation. Further studies are critical to examine additional potential therapeutic targets and more specific treatments based on the cause and progress of the disease.

Using the Mouse to Model Human Diseases: Cognitive Impairment in Systemic Lupus Erythematosus.

In this 2020 Dunlop-Dottridge Lecture, the authors discuss cognitive impairment (CI), one of the most prevalent neuropsychiatric syndromes in systemic lupus erythematosus (SLE). Patients often report CI as the most bothersome disease-related manifestation, with a great effect on their quality of life. Nevertheless, studies focusing on CI remain scarce and no effective targeted therapy has been identified. We herein present murine models of CI in SLE with insights into the pathogenesis of this condition as well as the role of the renin angiotensin system in microglial activation. We will discuss the role of neuroimaging as a useful objective assessment tool, describing our experience in previous and ongoing clinical trials of CI in patients with SLE.

Effect of Patellar Electrocautery Neurectomy on Postoperative Pain among Patients Referred for Total Knee Arthroplasty.

BACKGROUND: Anterior knee pain is a major problem in total knee arthroplasty (TKA). It is accepted that anterior knee pain (AKP) often contributes to a patellofemoral etiology; however, its etiology or treatment is not understood completely. Disabling pain receptors by electrocautery could theoretically lead to anterior knee area denervation. The present study aimed to evaluate the pain post-patellar denervation (PD) with electrocautery in TKA. MATERIALS AND METHODS: Clinical results for 92 patients who underwent TKA (58 women, 34 men; mean age 67.5 years) were analyzed. In addition to removal of all osteophytes, PD by electrocautery was performed on patella of treatment group (n = 46) and debridement alone including removing of all osteophytes was performed on the control group (n = 46). Knee Society System (KSS) score, patella score (PS), and visual analog scale (VAS) were used to determine pre- and post-operative AKP. RESULTS: The follow-up duration was 10 months. No revision or reoperations were performed. There were no patellar fractures. On all parameters (KSS score, PS, and VAS), there was a statistically significant pre- to post-operative difference in favor of the denervation group only 3 weeks after operation; however, there was no statistically difference postoperation on other follow-ups (3, 6, and 10 months). CONCLUSIONS: PD with electrocautery could reduce AKP in TKA without patellar resurfacing only in a short-term period postoperation.

New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut.

E. coli releases a 33 amino acid peptide melanocortin-like peptide of E. coli (MECO-1) that is identical to the C-terminus of the E. coli elongation factor-G (EF-G) and has interesting similarities to two prominent mammalian melanocortin hormones, alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropin (ACTH). Note that MECO-1 lacks HFRW, the common pharmacophore of the known mammalian melanocortin peptides. MECO-1 and the two hormones were equally effective in severely blunting release of cytokines (HMGB1 and TNF) from macrophage-like cells in response to (i) endotoxin (lipopolysaccharide) or (ii) pro-inflammatory cytokine HMGB-1. The in vitro anti-inflammatoty effects of MECO-1 and of alpha-MSH were abrogated by (i) antibody against melanocortin-1 receptor (MC1R) and by (ii) agouti, an endogenous inverse agonist of MC1R. In vivo MECO-1 was even more potent than alpha-MSH in rescuing mice from death due to (i) lethal doses of LPS endotoxin or (ii) cecal ligation and puncture, models of sterile and infectious sepsis, respectively.

MicroRNA Expression Relating to Dietary-Induced Liver Steatosis and NASH.

Health issues associated with excessive caloric intake and sedentary lifestyle are driving a modern "epidemic" of liver disease. Initially presenting in the clinic as an excessive accumulation of fat within hepatocyte cells (steatosis), the progression to more severe non-alcoholic steatohepatitis (NASH) in which liver damage and inflammation are overt features, is becoming increasingly common. Often developing as a sequela of obesity, non-alcoholic fatty liver disease (NAFLD) arises in almost one-third of people initially carrying excess hepatic fat and is likely the result of the liver's limited capacity to cope with the modern-day levels of dietary fatty acids circulating in the blood. While routine imaging can readily assess the presence and level of "extra-hepatic fat", a proper diagnosis of disease progression to NASH is currently only possible by liver biopsy. A general reluctance to undergo such screening means that the prevalence of NASH is likely to be under reported and, thus, risk assessment for future metabolic syndrome (MetS) markedly compromised. The seemingly inevitable progression to overt insulin resistance that characterizes MetS may in part be the consequence of the body's attempt to cope with NAFLD by driving systemic insulin sensitivity and, thus, fatty acid breakdown. The potential significance of miRNAs in both physiological homeostasis and pathogenesis is increasingly appreciated and in the liver may contribute specifically to the regulation of lipid pathways and NAFLD progression. As such, they may have utility as molecular indicators for the accurate profiling of both initial risk and disease progression from simple steatosis to NASH, and further to fibrosis/cirrhosis.

Leucine alters hepatic glucose/lipid homeostasis via the myostatin-AMP-activated protein kinase pathway - potential implications for nonalcoholic fatty liver disease.

BACKGROUND: Elevated plasma levels of the branched-chain amino acid (BCAA) leucine are associated with obesity and insulin resistance (IR), and thus the propensity for type 2 diabetes mellitus development. However, other clinical studies suggest the contradictory view that leucine may in fact offer a degree of protection against metabolic syndrome. Aiming to resolve this apparent paradox, we assessed the effect of leucine supplementation on the metabolism of human hepatic HepG2 cells. RESULTS: We demonstrate that pathophysiological leucine appears to be antagonistic to insulin, promotes glucose uptake (and not glycogen synthesis), but results in hepatic cell triglyceride (TG) accumulation. Further, we provide evidence that myostatin (MSTN) regulation of AMP-activated protein kinase (AMPK) is a key pathway in the metabolic effects elicited by excess leucine. Finally, we report associated changes in miRNA expression (some species previously linked to metabolic disease etiology), suggesting that epigenetic processes may contribute to these effects. CONCLUSIONS: Collectively, our observations suggest leucine may be both 'friend' and 'foe' in the context of metabolic syndrome, promoting glucose sequestration and driving lipid accumulation in liver cells. These observations provide insight into the clinical consequences of excess plasma leucine, particularly for hyperglycemia, IR and nonalcoholic fatty liver disease (NAFLD).