Modulation of Inflammation by Extracellular Granzyme A.

Kim R Van Daalen,Josephine F Reijneveld,Niels Bovenschen

doi:10.3389/fimmu.2020.00931

Kim R Van Daalen, Josephine F Reijneveld + Show 1 more

Open Access

https://doi.org/10.3389/fimmu.2020.00931

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Abstract

Granzyme A (GrA) has long been recognized as one of the key players in the induction of cell death of neoplastic, foreign or infected cells after granule delivery by cytotoxic cells. While the cytotoxic potential of GrA is controversial in current literature, accumulating evidence now indicates roles for extracellular GrA in modulating inflammation and inflammatory diseases. This paper aims to explore the literature presenting current knowledge on GrA as an extracellular modulator of inflammation by summarizing (i) the presence and role of extracellular GrA in several inflammatory diseases, and (ii) the potential molecular mechanisms of extracellular GrA in augmenting inflammation.

Highlights

Granzymes are a family of homologous serine proteases primarily expressed by a collective of cytotoxic cells, i.e., cytotoxic T lymphocytes (CTLs), γδ T cells, natural killer (NK) cells, NK-T cells
GrA−/− mice injected with a sublethal dose of the bacterium clear the infection like wild-type (WT) mice, while GrB−/− mice, perforin−/− mice and mice depleted of cytotoxic CD8+ T cells do not
GrA−/− mice have a higher survival rate compared with WT mice and perforin or GrB depleted mice, which is correlated with a significant reduction in the levels of the cytokines IL-1α, IL-1β, IL-6

Summary

Introduction

Granzymes are a family of homologous serine proteases primarily expressed by a collective of cytotoxic cells, i.e., cytotoxic T lymphocytes (CTLs), γδ T cells, natural killer (NK) cells, NK-T cells. Apoptosis mediated by cytotoxic cells is induced via engagement of the death receptor pathway or the granule secretory pathway [2]. Whereas the death receptor pathway involves death cell surface receptor-ligand interaction and caspase recruitment, the granule secretory pathway delivers granzymes through a process involving the aid of perforin, a pore-forming protein, to target cells [3, 4]. Perforin provides granzymes access to the cytosol of the targets cell, where granzymes cleave their cohort of substrates to promote programmed cell death [5, 6]. Human granzymes are highly homologous in amino acid sequence (40%), they variate in their primary substrate specificity (amino acid after which the granzyme preferably cleaves) resulting in a unique granzyme degradome [9]

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