Abstract

Cysteine cathepsins are key regulators of the innate and adaptive arms of the immune system. Their expression, activity, and subcellular localization are associated with the distinct development and differentiation stages of immune cells. They promote the activation of innate myeloid immune cells since they contribute to toll-like receptor signaling and to cytokine secretion. Furthermore, they control lysosomal biogenesis and autophagic flux, thus affecting innate immune cell survival and polarization. They also regulate bidirectional communication between the cell exterior and the cytoskeleton, thus influencing cell interactions, morphology, and motility. Importantly, cysteine cathepsins contribute to the priming of adaptive immune cells by controlling antigen presentation and are involved in cytotoxic granule mediated killing in cytotoxic T lymphocytes and natural killer cells. Cathepins'aberrant activity can be prevented by their endogenous inhibitors, cystatins. However, dysregulated proteolysis contributes significantly to tumor progression also by modulation of the antitumor immune response. Especially tumor-associated myeloid cells, such as tumor-associated macrophages and myeloid-derived suppressor cells, which are known for their tumor promoting and immunosuppressive functions, constitute the major source of excessive cysteine cathepsin activity in cancer. Since they are enriched in the tumor microenvironment, cysteine cathepsins represent exciting targets for development of new diagnostic and therapeutic moieties.

Highlights

  • Lysosomes are specialized recycling organelles responsible for the breakdown of material that enters endosomes or autophagosomes

  • Extracellular cystatin C binds TGF-β, an important immunomodulatory cytokine, and prevents TGF-β signaling by blocking access to its receptor [94]. These findings indicate that cystatins possess active sites and regulate functions that are unrelated to proteolysis

  • Understanding the differential regulation of cysteine cathepsins’ expression and activity in normal and pathologically activated myeloid cells is of vital importance

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Summary

Introduction

Lysosomes are specialized recycling organelles responsible for the breakdown of material that enters endosomes or autophagosomes. Cathepsin K modulates the immune response in a SCID-hu mouse bone tumor model by recruiting TAM via CCL2 and promoting expression of cathepsin B and COX2 [42]. Combined activation of hematopoietic cell-specific transcription factors IRF8 and PU.1 promotes high expression of cystatin C in mouse macrophages and in a subpopulation of CD8+ dendritic cells [90].

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