A Role for Stefin B (Cystatin B) in Inflammation and Endotoxemia

Maher, Katarina; Kokelj, Barbara Jerič; Butinar, Miha; Mikhaylov, Georgy; Manček-Keber, Mateja; Stoka, Veronika; Vasiljeva, Olga; Turk, Boris; Grigoryev, Sergei A.; Kopitar-Jerala, Nataša

doi:10.1074/jbc.m114.609396

Cited by 59 publications

(66 citation statements)

References 67 publications

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“…In fact, lower serum levels of cystatin C, considered the “dominant” cystatin (77), are associated with numerous inflammatory conditions (66), including sterile inflammatory arterial disease (78). Furthermore, cystatin B deficiency in mice exacerbated LPS-induced sepsis and elevated IL-1β levels in the serum (79). This latter study demonstrated higher caspase-1 and/or -11 activity and mitochondrial ROS, suggesting that loss of cystatin B increased inflammasome activation (79).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, cystatin B deficiency in mice exacerbated LPS-induced sepsis and elevated IL-1β levels in the serum (79). This latter study demonstrated higher caspase-1 and/or -11 activity and mitochondrial ROS, suggesting that loss of cystatin B increased inflammasome activation (79). However, the authors noted that there were no signs of LMD or elevated cathepsin activity in the cytosol, and effects on pro-IL-1β were not measured.…”

Section: Discussionmentioning

confidence: 99%

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Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

Orlowski

Colbert

Sharma

et al. 2015

The Journal of Immunology

225

201

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Sterile particles induce robust inflammatory responses that underlie the pathogenesis of diseases like silicosis, gout and atherosclerosis. A key cytokine mediating this response is IL-1β. The generation of bioactive IL-1β by sterile particles is mediated by the NLRP3 inflammasome, although exactly how this occurs is incompletely resolved. Prior studies have found that the cathepsin B inhibitor, Ca074Me, suppresses this response, supporting a model whereby ingested particles disrupt lysosomes and release cathepsin B into the cytosol, somehow activating NLRP3. However, reports that cathepsin B-deficient macrophages have no defect in particle-induced IL-1β generation have questioned cathepsin B’s involvement. Here, we examine the hypothesis that multiple redundant cathepsins (not just cathepsin B) mediate this process by evaluating IL-1β generation in murine macrophages, singly or multiply deficient in cathepsins B, L, C, S and X. Using an activity-based probe, we measure specific cathepsin activity in living cells, documenting compensatory changes in cathepsin-deficient cells, and Ca074Me’s dose-dependent cathepsin inhibition profile is analyzed in parallel with its suppression of particle-induced IL-1β secretion. Also, we evaluate endogenous cathepsin inhibitors, cystatins C and B. Surprisingly, we find that multiple redundant cathepsins, inhibited by Ca074Me and cystatins, promote pro-IL-1β synthesis, and we provide the first evidence that cathepsin X plays a non-redundant role in non-particulate NLRP3 activation. Finally, we find cathepsin inhibitors selectively block particle-induced NLRP3 activation, independently of suppressing pro-IL-1β synthesis. Altogether, we demonstrate that both small molecule and endogenous cathepsin inhibitors suppress particle-induced IL-1β secretion, implicating roles for multiple cathepsins in both pro-IL-1β synthesis and NLRP3 activation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

Orlowski

Colbert

Sharma

et al. 2015

The Journal of Immunology

225

201

View full text Add to dashboard Cite

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“…Enzymatic activities and proteins resembling, related, or being even identical with endo-lysosomal proteases have been detected in the cytoplasm, the mitochondria, and the nucleus (Dall and Brandstetter 2013;Duncan et al 2008;Goulet et al 2004;Haugen et al 2013;Maher et al 2014;Sullivan et al 2009;Tamhane et al 2014;Tedelind et al 2010). Below, we will outline possible pathways and cell biologically meaningful processes in an attempt to explain the occurrence of endolysosomal proteases and/or variants thereof in such highly unexpected locations.…”

Section: Endo-lysosomal Cysteine Peptidases: Myths and Common Questionsmentioning

confidence: 99%

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

et al. 2014

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Proteases play essential roles in protein degradation, protein processing, and extracellular matrix remodeling in all cell types and tissues. They are also involved in protein turnover for maintenance of homeostasis and protein activation or inactivation for cell signaling. Proteases range in function and specificity, with some performing distinct substrate cleavages, while others accomplish proteolysis of a wide range of substrates. As such, different cell types use specialized molecular mechanisms to regulate the localization of proteases and their function within the compartments to which they are destined. Here, we focus on the cysteine family of cathepsin proteases and legumain, which act predominately within the endo-lysosomal pathway. In particular, recent knowledge on cysteine cathepsins and their primary regulator legumain is scrutinized in terms of their trafficking to endo-lysosomal compartments and other less recognized cellular locations. We further explore the mechanisms that regulate these processes and point to pathological cases which arise from detours taken by these proteases. Moreover, the emerging biological roles of specific forms and variants of cysteine cathepsins and legumain are discussed. These may be decisive, pathogenic, or even deadly when localizing to unusual cellular compartments in their enzymatically active form, because they may exert unexpected effects by alternative substrate cleavage. Hence, we propose future perspectives for addressing the actions of cysteine cathepsins and legumain as well as their specific forms and variants. The increasing knowledge in non-canonical aspects of cysteine cathepsin- and legumain-mediated proteolysis may prove valuable for developing new strategies to utilize these versatile proteases in therapeutic approaches.

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“…CSTB is highly expressed in immune cells, e.g., in blood leukocytes, hepatic lymphocytes, placental macrophages, and microglia [5–9], and it is upregulated in vitro by pro-inflammatory stimulation [8, 10, 11]. In immune cells, the function of CSTB has been linked to chemotaxis [8], expression and secretion of cytokines, and release of nitric oxide [10, 12, 13], implying a role in the immune response. CSTB function has also been associated with diverse cellular processes, such as regulation of apoptosis [14, 15], bone resorption [16, 17], protection of neurons from oxidative stress [18], and cell cycle progression [19].…”

Section: Introductionmentioning

confidence: 99%

Brain inflammation is accompanied by peripheral inflammation in Cstb −/− mice, a model for progressive myoclonus epilepsy

Окунева

Körber

et al. 2016

J Neuroinflammation

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Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited childhood-onset neurodegenerative disorder, characterized by myoclonus, seizures, and ataxia. Mutations in the cystatin B gene (CSTB) underlie EPM1. The CSTB-deficient (Cstb −/−) mouse model recapitulates key features of EPM1, including myoclonic seizures. The mice show early microglial activation that precedes seizure onset and neuronal loss and leads to neuroinflammation. We here characterized the inflammatory phenotype of Cstb −/− mice in more detail. We found higher concentrations of chemokines and pro-inflammatory cytokines in the serum of Cstb −/− mice and higher CXCL13 expression in activated microglia in Cstb −/− compared to control mouse brains. The elevated chemokine levels were not accompanied by blood-brain barrier disruption, despite increased brain vascularization. Macrophages in the spleen and brain of Cstb −/− mice were predominantly pro-inflammatory. Taken together, these data show that CXCL13 expression is a hallmark of microglial activation in Cstb −/− mice and that the brain inflammation is linked to peripheral inflammatory changes, which might contribute to the disease pathology of EPM1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0764-7) contains supplementary material, which is available to authorized users.

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A Role for Stefin B (Cystatin B) in Inflammation and Endotoxemia

Cited by 59 publications

References 67 publications

Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

Multiple Cathepsins Promote Pro–IL-1β Synthesis and NLRP3-Mediated IL-1β Activation

Proteolysis mediated by cysteine cathepsins and legumain—recent advances and cell biological challenges

Brain inflammation is accompanied by peripheral inflammation in Cstb −/− mice, a model for progressive myoclonus epilepsy

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