An international collaborative study led by U.S and Chinese scientists was the first to show that the extracellular autophagy regulator, sequestosome-1 (SQSTM1), mediates septic death in mice by activating insulin receptor (INSR) signaling in macrophages and monocytes.

Targeting the SQSTM1-INSR axis may therefore help to prevent and/or treat life-threatening sepsis, despite the failure of different anticytokine therapies in this regard, the authors reported in the October 19, 2020, edition of Nature Microbiology.

Sepsis is the most common cause of organ failure and death in intensive care patients worldwide, due to a dysregulated host response to infection by bacteria, predominately Gram-negatives, fungi or viruses.

Bacterial infections are characterized by excessive innate immune system activation upregulating the release of proinflammatory cytokines, metabolic dysregulation, immunosuppression and multiple organ failure.

However, treatment options for sepsis and septic shock are limited, noted study co-leader Rui Kang, an associate professor of surgery at the University of Texas Southwestern (UTSW) Medical Center in Dallas.

"The success of sepsis treatment depends on early diagnosis and start of appropriate antibiotic and supportive therapy, but there are no specific effective therapeutic drugs available for clinical use," said Kang.

"Treatment could be improved by the development of new drugs targeting dysfunctional immunometabolic pathways such as those promoting autophagy, which are a central hallmark of sepsis," she told BioWorld Science.

Autophagy

A lysosome-dependent degradation pathway, autophagy plays key roles in inflammation, immunity and disease by eliminating invasive pathogens, inhibiting inflammasome activation and by mediating cytokine release.

Autophagy is controlled by autophagy-related (ATG) proteins and autophagy receptors such as SQSTM1, also known as p62.

Besides intracellular ATG function, some ATGs have been detected in patients with chronic CNS inflammation or diabetic kidney diseases, while elevated serum SQSTM1 levels are independent risk factors for patients with steatosis and liver inflammation.

These findings indicate the emerging role of extracellular autophagy regulators in disease, with SQSTM1 regulating innate immunity via autophagy-dependent and -independent functions.

For example, intracellular SQSTM1 binds to tumor necrosis factor receptor-associated factor 6 (TRAF6) to activate nuclear factor kappa B (NF-kappaB), a key regulator of immunity.

However, compared with intracellular SQSTM1, the molecular mechanism of innate immunity mediated by extracellular SQSTM1 remains unclear.

This prompted the new study co-led by Kang, Daoling Tang, an associate professor of surgery at UTSW, and Jianxin Jiang, a professor in the Institute of Surgery Research at Daping Hospital in Chongqing, China, which investigated the role of SQSTM1 in sepsis.

"Gram-negative bacteria are the leading cause of clinical sepsis, so we investigated whether lipopolysaccharide, the major component of Gram-negative outer membranes, could trigger the release of SQSTM1 in macrophages and monocytes," explained Kang.

"Gram-negative infections not only cause these myeloid cells to secrete proinflammatory cytokines, but were also shown to promote pyroptotic cell death of these immune cells, releasing inflammatory endogenous damage-associated molecular pattern (DAMP) molecules.

"Although the common mediator of these processes has remained poorly understood, our research shows that SQSTM1 is a mediator of these passive and active processes, which can lead to septic death, suggesting SQSTM1 inhibition could significantly prevent septic death," she told BioWorld Science.

Moreover, extracellular SQSTM1 was shown to bind to INSR, which in turn activated an NF-kappaB-dependent metabolic pathway, leading to aerobic glycolysis and macrophage polarization.

"The interaction between aerobic glycolysis and macrophage polarization is an important immunometabolic process contributing to sepsis," said Kang.

"We have shown that extracellular SQSTM1 is an important mediator of immunometabolic disorder, so targeting its release and activity may correct dysfunctional immunometabolism in sepsis.

Indeed, intraperitoneal injection of an anti-SQSTM1-neutralizing monoclonal antibody (MAb) or knockout of the Insr gene in myeloid cells was shown to protect mice against lethal sepsis due to cecal ligation and infection by Escherichia coli or Streptococcus pneumoniae and endotoxemia.

"Mortality rates vary in different mouse models of sepsis, but generally anti-SQSTM1 MAb treatment or deletion of the Insr gene in myeloid cells increased the survival rate of severely septic mice from 25% to 75%," said Kang.

Circulating SQSTM1 and mRNA expression levels of Sqstm1 and Insr in peripheral blood mononuclear cells were also related to sepsis severity in 40 patients at Daping Hospital, assessed using sequential organ failure assessment (SOFA) and disseminated intravascular coagulation (DIC) scores.

"SOFA and DIC scores are important clinical indicators for evaluating the severity of sepsis," noted Kang.

"We showed that the SOFA and DIC scores significantly correlated with the concentration of circulating SQSTM1 and mRNA expression levels of Sqstm1 and Insr in peripheral blood mononuclear cells from patients with bacterial sepsis."

Concluding, said Kang, "our research suggests that blocking the release and intracellular activity of SQSTM1 may represent an important new strategy for the treatment of patients with sepsis.

"We will now use drug screening to identify new compounds with which to block the release and activity of SQSTM1, then evaluate their effects on experimental sepsis," she said.

"However, sepsis can also be caused by viral infections and, given the current COVID-19 pandemic, we are also keen to investigate whether serum SQSTM1 may be a biomarker for assessing the severity of SARS-CoV-2 viral infection." (Zhou, B. et al. Nat Microbiol 2020, Advanced publication).