Cathepsins are the most abundant lysosomal proteases that are mainly found in acidic endo/lysosomal compartments where they play a vital role in intracellular protein degradation, energy metabolism, and immune responses among a host of other functions. The discovery that cathepsins are secreted and remain functionally active outside of the lysosome has caused a paradigm shift. Contemporary research has unraveled many versatile functions of cathepsins in extralysosomal locations including cytosol and extracellular space. Nevertheless, extracellular cathepsins are majorly upregulated in pathological states and are implicated in a wide range of diseases including cancer and cardiovascular diseases. Taking advantage of the dierential expression of the cathepsins during pathological conditions, much research is focused on using cathepsins as diagnostic markers and therapeutic targets. A tailored therapeutic approach using selective cathepsin inhibitors is constantly emerging to be safe and ecient. Moreover, recent development of proteomic-based approaches for the identification of novel physiological substrates oers a major opportunity to understand the mechanism of cathepsin action. In this review, we summarize the available evidence regarding the role of cathepsins in health and disease, discuss their potential as biomarkers of disease progression, and shed light on the potential of extracellular cathepsin inhibitors as safe therapeutic tools.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, yet the pathogenesis of NAFLD is only partially understood. Here, we investigated the role of the gut bacteria in NAFLD by stimulating the gut bacteria via feeding mice the fermentable dietary fiber, guar gum (GG), and suppressing the gut bacteria via chronic oral administration of antibiotics. GG feeding profoundly altered the gut microbiota composition, in parallel with reduced diet-induced obesity and improved glucose tolerance. Strikingly, despite reducing adipose tissue mass and inflammation, GG enhanced hepatic inflammation and fibrosis, concurrent with markedly elevated plasma and hepatic bile acid levels. Consistent with a role of elevated bile acids in the liver phenotype, treatment of mice with taurocholic acid stimulated hepatic inflammation and fibrosis. In contrast to GG, chronic oral administration of antibiotics effectively suppressed the gut bacteria, decreased portal secondary bile acid levels, and attenuated hepatic inflammation and fibrosis. Neither GG nor antibiotics influenced plasma lipopolysaccharide levels. In conclusion, our data indicate a causal link between changes in gut microbiota and hepatic inflammation and fibrosis in a mouse model of NAFLD, possibly via alterations in bile acids.

Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition, hallmarked by a disturbance in the bidirectional interaction between gut and brain. In general, the gut/brain axis involves direct and/or indirect communication via the central and enteric nervous system, host innate immune system, and particularly the gut microbiota. This complex interaction implies that IBD is a complex multifactorial disease. There is increasing evidence that stress adversely affects the gut/microbiota/brain axis by altering intestinal mucosa permeability and cytokine secretion, thereby influencing the relapse risk and disease severity of IBD. Given the recurrent nature, therapeutic strategies particularly aim at achieving and maintaining remission of the disease. Alternatively, these strategies focus on preventing permanent bowel damage and concomitant long-term complications. In this review, we discuss the gut/microbiota/brain interplay with respect to chronic inflammation of the gastrointestinal tract and particularly shed light on the role of stress. Hence, we evaluated the therapeutic impact of stress management in IBD.

Due to the obesity epidemic, non-alcoholic steatohepatitis (NASH) is a prevalent liver disease, characterized by fat accumulation and inflammation of the liver. However, due to a lack of mechanistic insight, diagnostic and therapeutic options for NASH are poor. Recent evidence has indicated cathepsin D (CTSD), a lysosomal enzyme, as a marker for NASH. Here, we investigated the function of CTSD in NASH by using an in vivo and in vitro model. In addition to diminished hepatic inflammation, inhibition of CTSD activity dramatically improved lipid metabolism, as demonstrated by decreased plasma and liver levels of both cholesterol and triglycerides. Mechanistically, CTSD inhibition resulted in an increased conversion of cholesterol into bile acids and an elevated excretion of bile acids via the feces, indicating that CTSD influences lipid metabolism. Consistent with these findings, treating Wt BMDMs with PepA in vitro showed a similar decrease in inflammation and an analogous effect on cholesterol metabolism. Conclusion: CTSD is a key player in the development of hepatic inflammation and dyslipidemia. Therefore, aiming at the inhibition of the activity of CTSD may lead to novel treatments to combat NASH.

Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro‐inflammatory cytokines interleukin 1β (IL‐1β) and interleukin 18 (IL‐18) via activation of caspase‐1/11. Previously, it was shown that complete caspase‐1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage‐specific caspase‐1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase‐1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase‐1/11 activation to atherosclerosis development, Ldlr^−/− mice received a transplant (tp) of wild‐type (WT) or caspase‐1/11^−/− bone marrow, to create WT‐tp mice and caspase‐1/11^−/−‐tp mice, and fed a high‐fat, high‐cholesterol diet for 12 weeks. Our results showed an increase in anti‐inflammatory blood leukocytes in caspase‐1/11^−/−‐tp mice compared with WT‐tp mice, as indicated by a decreased level of Ly6C^high monocytes and an increased level of Ly6C^low monocytes. In line with our hypothesis, hematopoietic deletion of caspase‐1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase‐1/11^−/−‐tp mice. Our data indicate that hematopoietic caspase‐1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression.

Aims/hypothesis: Insulin resistance in skeletal muscle and liver plays a major role in the pathophysiology of type 2 diabetes. The hyperinsulinaemic–euglycaemic clamp is considered the gold standard for assessing peripheral and hepatic insulin sensitivity, yet it is a costly and labour-intensive procedure.Therefore, easy-to-measure, cost-effective approaches to determine insulin sensitivity are needed to enable organ-specific interventions. Recently, evidence emerged that plasma cathepsin D (CTSD) is associated with insulin sensitivity and hepatic inflammation. Here, we aimed to investigate whether plasma CTSD is associated with hepatic and/or peripheral insulin sensitivity in humans.Methods: As part of two large clinical trials (one designed to investigate the effects of antibiotics, and the other to investigate polyphenol supplementation, on insulin sensitivity), 94 overweight and obese adults (BMI 25–35 kg/m²) previously underwent a two-step hyperinsulinaemic–euglycaemic clamp (using [6,6-²H₂]glucose) to assess hepatic and peripheral insulin sensitivity (per cent suppression of endogenous glucose output during the low-insulin-infusion step, and the rate of glucose disappearance during high-insulin infusion [40 mU/(m²× min)], respectively). In this secondary analysis, plasma CTSD levels, CTSD activity and plasma inflammatory cytokines were measured.Results: Plasma CTSD levels were positively associated with the proinflammatory cytokines IL-8 and TNF-α (IL-8: standardised β = 0.495,p< 0.001; TNF-α: standardised β = 0.264,p= 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised β = −0.206,p= 0.043), independent of age, sex, BMI and waist circumference, but it was not associated with peripheral insulin sensitivity. However, plasma IL-8 and TNF-α were not significantly correlated with hepatic insulin sensitivity.Conclusions/interpretation: We demonstrate that plasma CTSD activity, but not systemic inflammation, is inversely related to hepatic insulin sensitivity, suggesting that plasma CTSD activity may be used as a non-invasive marker for hepatic insulin sensitivity in humans.