Mitochondria play a critical role in cell survival and death. Mitochondrial recovery during inflammatory processes such as sepsis is associated with cell survival. Recovery of cellular respiration, mitochondrial biogenesis and function requires coordinated expression of transcription factors encoded by nuclear and mitochondrial genes, including mitochondrial transcription factor A (T-fam) and cytochrome c oxidase (COX, complex IV). LPS elicits strong host defenses in mammals with pronounced inflammatory responses but also triggers activation of survival pathways such as AKT pathway. AKT/PKB is a serine/threonine protein kinase playing an important role in cell survival, protein synthesis, and controlled inflammation in response to TLRs. Hence, we investigated the role of LPS mediated AKT activation in mitochondrial bioenergetics and function in cultured murine macrophages (B6-MCL) and bone marrow derived macrophages. We show that LPS challenge led to increased expression of T-fam and COX subunit I and IV in a time dependent manner through early phosphorylation of the PI3kinase/AKT pathway. PI3K/AKT pathway inhibitors abrogated LPS mediated T-fam and COX induction. Lack of induction was associated with decreased ATP production, increased proinflammatory cytokines (TNF-α), nitric oxide production and cell death. The TLR4 mediated AKT activation and mitochondrial biogenesis required activation of adaptor protein MyD88 and Toll-IL-1R-containing adaptor inducing IFN-β (TRIF). Importantly, using a genetic approach, we show that the AKT1 isoform is pivotal in regulating mitochondrial biogenesis in response to TLR4 agonist.

Sarcoidosis is a complex systemic granulomatous disease of unknown etiology characterized by the presence of activated macrophages and Th1/Th17 effector cells. Data mining of our RNA-Seq analysis of CD14+monocytes showed enrichment for metabolic and hypoxia inducible factor (HIF) pathways in sarcoidosis. Further investigation revealed that sarcoidosis macrophages and monocytes exhibit higher protein levels for HIF-α isoforms, HIF-1β, and their transcriptional co-activator p300 as well as glucose transporter 1 (Glut1). In situ hybridization of sarcoidosis granulomatous lung tissues showed abundance of HIF-1α in the center of granulomas. The abundance of HIF isoforms was mechanistically linked to elevated IL-1β and IL-17 since targeted down regulation of HIF-1α via short interfering RNA or a HIF-1α inhibitor decreased their production. Pharmacological intervention using chloroquine, a lysosomal inhibitor, decreased lysosomal associated protein 2 (LAMP2) and HIF-1α levels and modified cytokine production. These data suggest that increased activity of HIF-α isoforms regulate Th1/Th17 mediated inflammation in sarcoidosis.

Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine that plays a major role in inflammatory diseases as well as cancer. The inflammatory response after Toll-like receptor (TLR) 4 activation is tightly regulated through phosphorylation of MAP kinases, including p38 and JNK pathways. The activation of MAP kinases is negatively regulated by MAPK phosphatases (MKPs). MKP-1 preferentially dephosphorylates p38 and JNK. IL-1β is regulated through the activation of MAPK, including p38 as well as several transcription factors. The oxygen-sensitive transcription factor HIF-1α is a known transcription factor for several inflammatory cytokines including IL-1β and IL-6. Here, we report that MKP-1 regulates HIF-1α expression in response to LPS. MKP-1 deficient bone marrow derived macrophages (BMDMs) exhibited increased reactive oxygen species (ROS) production and higher HIF-1α expression. In contrast, the expression of all three isoforms of prolyl hydroxylases (PHDs), which are important in destabilizing HIF-1α through hydroxylation, were significantly decreased in MKP-1 deficient BMDMs. LPS challenge of MKP-1 deficient BMDMs led to a substantial increase in IL-1β production. An inhibitor of HIF-1α significantly decreased LPS mediated IL-1β production both at the transcript and protein levels. Similarly, inhibition of p38 MAP kinase reduced LPS mediated pro-IL-1β and HIF-1α protein levels as well as ROS production in MKP-1 deficient BMDMs. These findings demonstrate a regulatory function for MKP-1 in modulating IL-1β expression through p38 activation, ROS production and HIF-1α expression.

Case series Patients: Male, 7-year-old • Female, 6-year-old • Male, 5-year-old Final Diagnosis: Multisystem inflammatory syndrome in children (MIS-C) Symptoms: Heart failure Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Unusual clinical course Background: Coronavirus disease 2019 (COVID-19) infection commonly presents as fever, cough, and shortness of breath in adults. Children are thought to have milder respiratory symptoms and to recover more quickly. We describe a new presentation of COVID-19 infection in children consisting of multisystem inflammation with decreased left ventricular function and evidence of lung disease. Case Reports: Three children presented with fever, conjunctivitis, dry and cracked lips, rash, and/or cervical lymphadenopathy for at least 5 days. Two of these children required mechanical ventilation, and 1 of the 2 needed extracorpo-real membrane oxygenation (ECMO) to support cardiorespiratory function. All of these children had moderate to severe hyponatremia and lymphopenia, which is usually seen in COVID-19. They were treated with intravenous immunoglobulin and high-dose aspirin. All of the children recovered. Conclusions: Early recognition of children with multisystem inflammation is important because they are at increased risk for deterioration. Treatment with intravenous immunoglobulin and aspirin was used because this regimen has been shown to be beneficial in vasculitis of Kawasaki disease. The development of shock due to cardiac involvement may require ECMO.

The distribution of LH in serum of men on haemodialysis is more basic than in normal men. The greater the proportion of more acidic LH species, particularly those with a pI of between 5.50-6.25, the higher the ratio of LH bioactivity to immunoactivity and consequently testosterone levels.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Granulomatous inflammation in sarcoidosis may affect multiple organs, including the lungs, skin, CNS, and the eyes, leading to severe morbidity and mortality. The underlying mechanisms for sustained inflammation in sarcoidosis are unknown. We hypothesized that metabolic changes play a critical role in perpetuation of inflammation in sarcoidosis. 1H nuclear magnetic resonance (NMR)-based untargeted metabolomic analysis was used to identify circulating molecules in serum to discriminate sarcoidosis patients from healthy controls. Principal component analyses (PCA) were performed to identify different metabolic markers and explore the changes of associated biochemical pathways. Using Chenomx 7.6 NMR Suite software, we identified and quantified metabolites responsible for such separation in the PCA models. Quantitative analysis showed that the levels of metabolites, such as 3-hydroxybutyrate, acetoacetate, carnitine, cystine, homocysteine, pyruvate, and trimethylamine N-oxide were significantly increased in sarcoidosis patients. Interestingly, succinate, a major intermediate metabolite involved in the tricyclic acid cycle was significantly decreased in sarcoidosis patients. Application of integrative pathway analyses identified deregulation of butanoate, ketone bodies, citric cycle metabolisms, and transmethylation. This may be used for development of new drugs or nutritional modification.

The higher oxalate excretion in formula-fed infants is not because of the milk's oxalate concentration. Urinary citrate and sulfate excretion may be influenced by their higher concentrations in formula preparations, which may be of clinical importance in the population that is at risk for development of nephrocalcinosis.

Sepsis is the leading cause of death in the world. Recent reports suggest that in response to sepsis, metabolism of macrophages switches from oxidative phosphorylation to aerobic glycolysis. MAPK phosphatase (MKP)-1 (also known as DUSP1) localized in the nucleus and preferentially dephosphorylates p38 and JNK. MKP-1 controls the expression of numerous inflammatory genes and transcription factors, thereby regulating innate and adaptive immunity. MKP-1-deficient animals exhibit aberrant metabolic responses following bacterial infections with a markedly increased mortality in response to sepsis. Because metabolic reprogramming modulates immune responses to TLR-4 activation, we investigated the effect of MKP-1 deficiency on mitochondrial electron transport chains involved in oxidative phosphorylation and transcription factors regulating mitochondrial biogenesis. Mitochondrial biogenesis is regulated by three nuclear-encoded proteins, including transcription factor A (TFAM), nuclear respiratory factors (NRF-1), and peroxisome proliferator-activated receptor g coactivator-1-a (PGC-1a). We show that MKP-1-deficient mice/ macrophages exhibit, at baseline, higher expression of oxidative phosphorylation, TFAM, PGC-1a, and NRF-1 associated with increased respiration and production of reactive oxygen species as compared with wild-type mice. Surprisingly, MKP-1-deficient mice/macrophages responded to Escherichia coli sepsis or LPS with an impaired metabolic switch; despite enhanced glycolysis, a preserved mitochondrial function and biogenesis are exhibited. Furthermore, inhibition of p38 MAPK had no significant effect on TFAM and NRF-1 either in MKP-1-deficient macrophages or in wild-type macrophages. These findings support the conclusion that MKP-1 plays an important role in regulating proteins involved in glycolysis and oxidative phosphorylation and modulates expression of mitochondrial transcription factors.