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Extracellular SQSTM1 mediates bacterial septic death in mice through insulin receptor signalling.

ABSTRACT: Sepsis is the most common cause of death for patients in intensive care worldwide due to a dysregulated host response to infection. Here, we investigate the role of sequestosome-1 (SQSTM1/p62), an autophagy receptor that functions as a regulator of innate immunity, in sepsis. We find that lipopolysaccharide elicits gasdermin D-dependent pyroptosis to enable passive SQSTM1 release from macrophages and monocytes, whereas transmembrane protein 173-dependent TANK-binding kinase 1 activation results in the phosphorylation of SQSTM1 at Ser403 and subsequent SQSTM1 secretion from macrophages and monocytes. Moreover, extracellular SQSTM1 binds to insulin receptor, which in turn activates a nuclear factor kappa B-dependent metabolic pathway, leading to aerobic glycolysis and polarization of macrophages. Intraperitoneal injection of anti-SQSTM1-neutralizing monoclonal antibodies or conditional depletion of Insr in myeloid cells using the Cre-loxP system protects mice from lethal sepsis (caecal ligation and puncture or infection by Escherichia coli or Streptococcus pneumoniae) and endotoxaemia. We also report that circulating SQSTM1 and the messenger RNA expression levels of SQSTM1 and INSR in peripheral blood mononuclear cells are related to the severity of sepsis in 40 patients. Thus, extracellular SQSTM1 has a pathological role in sepsis and could be targeted to develop therapies for sepsis.

SUBMITTER: Zhou B

PROVIDER: S-EPMC7977680 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Extracellular SQSTM1 mediates bacterial septic death in mice through insulin receptor signalling.

Zhou Borong B Liu Jiao J Zeng Ling L Zhu Shan S Wang Haichao H Billiar Timothy R TR Kroemer Guido G Klionsky Daniel J DJ Zeh Herbert J HJ Jiang Jianxin J Tang Daolin D Kang Rui R

Nature microbiology 20201019 12

Sepsis is the most common cause of death for patients in intensive care worldwide due to a dysregulated host response to infection. Here, we investigate the role of sequestosome-1 (SQSTM1/p62), an autophagy receptor that functions as a regulator of innate immunity, in sepsis. We find that lipopolysaccharide elicits gasdermin D-dependent pyroptosis to enable passive SQSTM1 release from macrophages and monocytes, whereas transmembrane protein 173-dependent TANK-binding kinase 1 activation results ...[more]

PMID: 33077977

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Project description:Background & aimsObesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB(1)) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB(1) in insulin resistance and inhibition of insulin signaling pathways.MethodsWild-type mice and mice with disruption of CB(1) (CB(1)(-/-) mice) or with hepatocyte-specific deletion or transgenic overexpression of CB(1) were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB(1) in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression.ResultsThe HFD induced hepatic insulin resistance in wild-type mice, but not in CB(1)(-/-) mice or mice with hepatocyte-specific deletion of CB(1). CB(1)(-/-) mice that overexpressed CB(1) specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB(1), the HFD or CB(1) activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2α protein translation pathway. In hepatocytes isolated from human or mouse liver, CB(1) activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB(1) was up-regulated in samples from patients with nonalcoholic fatty liver disease.ConclusionsEndocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB(1)-mediated inhibition of insulin signaling and clearance.

Project description:AimsThe sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII)-induced hypertensive heart disease.Methods and resultsC57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. HR and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization-activated current (If), and L-type Ca2+ current (ICa,L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice.ConclusionsAngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to up-regulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.

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Extracellular SQSTM1 mediates bacterial septic death in mice through insulin receptor signalling.

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Extracellular SQSTM1 mediates bacterial septic death in mice through insulin receptor signalling.

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