Cathepsin S inhibition suppresses autoimmune-triggered inflammatory responses in macrophages

Thanei, Sophia; Theron, Michel; Silva, Ana Patrícia; Reis, Bernhard; Branco, Leonore; Schirmbeck, Lucia; Kolb, Fabrice A.; Haap, Wolfgang; Schindler, Thomas; Trendelenburg, Marten

doi:10.1016/j.bcp.2017.10.001

Cited by 31 publications

(25 citation statements)

References 64 publications

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“…CTSS promotes systemic lupus erythematosus by regulating MHC class II-mediated T and B cell priming, germinal center formation and B cell maturation into plasma cells [85]. Inhibition of CTSS in these models could reduce lupus progression [85] and autoimmunetriggered inflammatory responses in macrophages [142]. Double knockout of Ctsb and Ctss modulates MHC-II processing and presentation of myelin oligodendrocyte glycoprotein, and protects mice from experimental autoimmune encephalomyelitis [86].…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

“…Both these antibody-based and protein-based therapies specifically target secreted CTSS. This could potentially help negate adverse effects associated with intracellular CTSS inhibition, namely, the blocking of MHC class II loading and subsequent cell-mediated immune responses [85,142]. As an alternative to the direct targeting of CTSS, therapeutic agents that target regulators of CTSS expression or activity, as discussed in the previous sections, may have therapeutic potential.…”

Section: Therapeutic Inhibition Of Ctssmentioning

confidence: 99%

“…A potential side effect associated with the inhibition of intracellular CTSS is the inhibition of MHC class II loading and subsequent decrease in adaptive immune responses. Inhibition of CTSS leads to decreased MHC class II expression on the surface of macrophages, monocytes and B cells and reduced expansion and activation of CD4+ T cells as well as suppressed B cell maturation to plasma cells [85,142]. While this may have a beneficial effect in the treatment of autoimmune conditions such as lupus or rheumatoid arthritis, in conditions associated with infection, including pulmonary conditions such as CF, there is a risk that this could hinder the body's ability to appropriately detect and respond to these infectious agents.…”

Section: Potential Adverse Effectsmentioning

confidence: 99%

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Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment. Proteases in pulmonary diseases Research in the last 60 years has demonstrated that proteases are critical contributors to pulmonary disease pathophysiology. Initially known as protein-degrading enzymes with a restricted spectrum of substrates, recent studies have revealed that the diversity of protease substrates and biological effects triggered by their processing is vast [1, 2]. Proteases are primarily known for their matrix degradation capabilities, but also play significant roles in other biological mechanisms such as angiogenesis, growth factor bioavailability, cytokine processing, receptor shedding and activation, as well as cellular processes including migration, proliferation, invasion, and survival [3]. Importantly, protease activity requires tight regulation, and disruption of the close interplay between proteases, substrates and inhibitors may contribute to the pathogenesis and progression of a variety of pulmonary diseases, including muco-inflammatory diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), as well as infection [4]. In pulmonary diseases with a high neutrophil burden such as CF, a protease:antiprotease imbalance is frequently observed. The activity of proteases such as neutrophil elastase (NE) in the respiratory tract is regulated by antiproteases, such as α1-antitrypsin (A1AT) [5], secretory leukoprotease inhibitor (SLPI) [6] and elafin [7]. However, in diseases like CF, the antiproteases are overburdened by their cognate proteases and this imbalance can result in chronic airway inflammation, decreased mucociliary clearance, mucus obstruction, extracellular matrix (ECM) remodeling, increased susceptibility to infection and impaired immune responses [8].

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Section: Autoimmune Diseasesmentioning

confidence: 99%

Section: Therapeutic Inhibition Of Ctssmentioning

confidence: 99%

Section: Potential Adverse Effectsmentioning

confidence: 99%

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Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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“…The reasons for investigating CTSS were that (1) the annotated substrate in the MEROPs database was a protein and not just a peptide (Fig. 1 b) and (2) CTSS has been linked previously not only to inflammatory processes 39 , 40 , but also directly to IL-6 41 , 42 . For an IL-6R protease, one would expect that it is expressed in similar cell types as the IL-6R.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the known cleavage site, we have mined the MEROPS database and found several proteases that could potentially cleave the IL-6R. We have concentrated on cathepsin S (CTSS), because its cellular expression profile matches the one of the IL-6R, it can be secreted from cells and would therefore be able to access the IL-6R, and finally because it is known to be involved in inflammatory reactions 39 , 40 . CTSS behaved in our initial peptide cleavage assays like ADAM17 and was able to release a biologically active sIL-6R in cellular assays that could bind IL-6 and perform trans-signaling on cells that lack the membrane-bound IL-6R and would thus without the sIL-6R not react to IL-6 alone.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro

Flynn

Garbers

Düsterhöft

et al. 2020

Sci Rep

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The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss−/− mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.

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Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro

Rabatscher

Trendelenburg

2022

Clin & Trans Imm

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Objectives Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease with complex pathogenic mechanisms. Complement C1q has been shown to play a major role in SLE, and autoantibodies against C1q (anti‐C1q) are strongly associated with SLE disease activity and severe lupus nephritis suggesting a pathogenic role for anti‐C1q. Whereas C1q alone has anti‐inflammatory effects on human monocytes and macrophages, C1q/anti‐C1q complexes favor a pro‐inflammatory phenotype. This study aimed to elucidate the inflammatory effects of anti‐C1q on peripheral blood mononuclear cells (PBMCs). Methods Isolated monocytes, isolated T cells and bulk PBMCs of healthy donors with or without concomitant T cell activation were exposed to C1q or complexes of C1q and SLE patient‐derived anti‐C1q (C1q/anti‐C1q). Functional consequences of C1q/anti‐C1q on cells were assessed by determining cytokine secretion, monocyte surface marker expression, T cell activation and proliferation. Results Exposure of isolated T cells to C1q or C1q/anti‐C1q did not affect their activation and proliferation. However, unspecific T cell activation in PBMCs in the presence of C1q/anti‐C1q resulted in increased TNF, IFN‐γ and IL‐10 secretion compared with C1q alone. Co‐culture and inhibition experiments showed that the inflammatory effect of C1q/anti‐C1q on PBMCs was due to a direct CD40–CD154 interaction between activated T cells and C1q/anti‐C1q‐primed monocytes. The CD40‐mediated inflammatory reaction of monocytes involves TRAF6 and JAK3‐STAT5 signalling. Conclusion In conclusion, C1q/anti‐C1q have a pro‐inflammatory effect on monocytes that depends on T cell activation and CD40–CD154 signalling. This signalling pathway could serve as a therapeutic target for anti‐C1q‐mediated inflammation.

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Cathepsin S inhibition suppresses autoimmune-triggered inflammatory responses in macrophages

Cited by 31 publications

References 64 publications

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro

Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro

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