BACKGROUND & AIMS The NLRP3 inflammasome induces inflammation in response to organ injury, but little is known about its regulation. Toll-like receptors (TLRs) provide the first signal required for activation of the inflammasome and stimulate aerobic glycolysis to generate lactate. We examined whether lactate and the lactate receptor, GPR81, regulate TLR induction of signal 1 and limit inflammasome activation and organ injury. METHODS Primary mouse macrophages and human monocytes were incubated with TLR4 agonists and lactate and assayed for levels of pro-IL1β, NLRP3, and CASP1; release of IL1β; and activation of NFκB and caspase 1. Small interfering (si)RNAs were used to reduce levels of GPR81andARRB2, and an NFκB luciferase reporter transgene was transfected in RAW 264.7 cells. Cell lysates were analyzed by immunoprecipitation with an antibody against GPR81. Acute hepatitis was induced in C56BL/6N mice by administration of lipopolysaccharaide (LPS) and D-galactosamine. Acute pancreatitis was induced by administration of LPS and caerulein. Some mice were given intraperitoneal injections of sodium lactate or siRNA against Gpr81. Activation of NFκB in tissue macrophages was assessed in mice that express a reporter transgene. RESULTS In macrophages and monocytes, increasing concentrations of lactate reduced TLR4-mediated induction of Il1B, Nlrp3, and Casp1; activation of NFκB; release of IL1β; and cleavage of CASP1. GPR81 and ARRB2 physically interacted and were required for these effects. Administration of lactate reduced inflammation and organ injury in mice with immune hepatitis; this reduction required Gpr81 dependence in vivo. Lactate also prevented activation of NFκB in macrophages of mice, and when given following injury, reduced the severity of acute pancreatitis and acute liver injury. CONCLUSIONS Lactate negatively regulates TLR induction of the NLRP3 inflammasome and production of IL1β, via ARRB2 and GPR81. Lactate could be a promising immunomodulatory therapy for patients with acute organ injury.

Coronavirus disease 2019 (Covid-19) is a predominantly respiratory illness caused by the SARS-CoV-2 virus. Data regarding prognostic factors are currently scarce given the novelty of the disease. Prognostic information would aid clinicians in managing patients, who are often left without data-driven guidelines to make important clinical decisions. It is known that lymphocytopenia, defined as an absolute lymphocyte count (ALC) < 1000 cells/µL, occurs in Covid-19 and may correlate with increased disease severity 1-5 ; indeed, lymphocytopenia is a common systemic manifestation of many viral illnesses 6 ; in particular, other coronaviruses like Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) have been demonstrated to cause lymphocytopenia. 2 However, few studies have examined whether lymphocytopenia found at the time of admission to the hospital is helpful in understanding the disease course. Here, we set out to study a cohort of patients admitted to the hospital diagnosed with Covid-19 to determine whether lymphocytopenia, found at the time of admission to the hospital, was associated with disease severity and other clinical outcomes.

Farooq A, Hoque R, Ouyang X, Farooq A, Ghani A, Ahsan K, Guerra M, Mehal WZ. Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a ␤-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol 307: G732-G740, 2014. First published August 7, 2014; doi:10.1152/ajpgi.00073.2014.-Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-Daspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a ␤-arrestin-2 NF-k␤ and JNK pathway and not via Ca 2ϩ mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.aspartate

The ability of tissue injury to result in inflammation is a well recognized phenomenon and is central to a number of common liver and pancreatic diseases including alcoholic steatohepatitis (ASH) and pancreatitis, as well as drug induced liver injury (DILI), non-alcoholic steatohepatitis (NASH), and pancreatitis from other causes. The requirements of extracellular damage associated molecules (DAMPs) and a cytosolic machinery labeled the inflammasome have been established in in-vitro culture systems and in-vivo disease models. This has provided a generic insight into the pathways involved, and the challenge now is to understand the specifics of these mechanisms in relation to the particular insults and organs involved. One reason for the excitement in this field is that a number of therapeutic candidates such a Toll-like receptor (TLR) antagonists and interleukin (IL)-1R antagonists are either approved or in clinical trials for other indications.

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Cytosolic and nuclear androgen, estrogen and progesterone receptor content was measured in the groups of 11 prostatic carcinoma (PCA) and 32 benign prostatic hypertrophy (BPH) samples. All BPH cases were positive for the cytosolic progesterone (PRc) and estrogen receptor (ERc), whereas only 85% of cases (23/27) contained the androgen receptor (ARc). Only those five patients who received estrogen treatment in the PCA group had detectable ARc. PRc was present in all of the PCA cases, whereas ERc could be detected in only 82% (9/11) of cases. Cytosolic contents of all three steroid receptors, however, were higher in the PCA group. The level of nuclear steroid receptors, although present in fewer cases in both groups, was higher than the cytoplasmic receptors. The serum profile of estradiol, cortisol, and prolactin was normal in both groups, whereas LH, FSH, and progesterone levels were higher than in normal adults. Serum testosterone level was within normal range in the BPH group, but it was significantly below normal (P less than 0.005) in PCA patients.

Prognostic markers are needed to understand the disease course and severity in patients with Covid-19. There is evidence that Covid-19 causes gastrointestinal symptoms and abnormalities in liver enzymes. We aimed to determine if hepatobiliary laboratory data could predict disease severity in patients with Covid-19. In this retrospective, single institution, cohort study that analyzed patients admitted to a community academic hospital with the diagnosis of Covid-19, we found that elevations of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline Phosphatase (AP) at any time during hospital admission increased the odds of ICU admission by 5.12 (95% CI: 1.55–16.89; p = 0.007), 4.71 (95% CI: 1.51–14.69; p = 0.01) and 4.12 (95% CI: 1.21–14.06, p = 0.02), respectively. Hypoalbuminemia found at the time of admission to the hospital was associated with increased mortality (p = 0.02), hypotension (p = 0.03), and need for vasopressors (p = 0.02), intubation (p = 0.01) and hemodialysis (p = 0.002). Additionally, there was evidence of liver injury: AST was significantly elevated above baseline in patients admitted to the ICU (54.2 ± 15.70 U/L) relative to those who were not (9.2 ± 4.89 U/L; p = 0.01). Taken together, this study found that hypoalbuminemia and abnormalities in hepatobiliary laboratory data may be prognostic factors for disease severity in patients admitted to the hospital with Covid-19.

Residues of dichlorodiphenyltrichloroethane (DDT) and its metabolites were monitored in leiomyomatous and normal human uterine tissue by gas-liquid chromatography (GLC). The metabolites detected were: 2,2-bis-(p-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), 2-(o-chlorophenyl)-2-(p-chlorophenyl)-1,1,1-trichloroethane (o,p'-DDT), 2,2-bis-(p-chlorophenyl)-1,1-dichloroethane (p,p'-DDD) and 2,2-bis-(p-chlorophenyl)-1,1,1-trichloroethane (p,p'-DDT). Total DDT ranged from 0.245 to 1.982 ppm, with a mean value of 0.845 ppm in leiomyomatous tissue. In normal human uterine tissue, total DDT ranged from 0.030 to 0.282 ppm, with a mean value of 0.103 ppm. Significantly higher levels of DDT and its metabolites in leiomyomatous tissue as compared to normal uterine tissue suggest their involvement in uterine leiomyomas. The data is discussed in the light of existing knowledge on estrogenic activity of DDT analogs and estrogen-influenced growth of uterine leiomyomas.