Granzyme B in Inflammatory Diseases: Apoptosis, Inflammation, Extracellular Matrix Remodeling, Epithelial-to-Mesenchymal Transition and Fibrosis

Abstract

Inflammation is strictly interconnected to anti-inflammatory mechanisms to maintain tissue homeostasis. The disruption of immune homeostasis can lead to acute and chronic inflammatory diseases, as cardiovascular, pulmonary, metabolic diseases and cancer. The knowledge of the mechanisms involved in the development and progression of these pathological conditions is important to find effective therapies. Granzyme B (GrB) is a serine protease produced by a variety of immune, non-immune and tumor cells. Apoptotic intracellular and multiple extracellular functions of GrB have been recently identified. Its capability of cleaving extracellular matrix (ECM) components, cytokines, cell receptors and clotting proteins, revealed GrB as a potential multifunctional pro-inflammatory molecule with the capability of contributing to the pathogenesis of different inflammatory conditions, including inflammaging, acute and chronic inflammatory diseases and cancer. Here we give an overview of recent data concerning GrB activity on multiple targets, potentially allowing this enzyme to regulate a wide range of crucial biological processes that play a role in the development, progression and/or severity of inflammatory diseases. We focus our attention on the promotion by GrB of perforin-dependent and perforin-independent (anoikis) apoptosis, inflammation derived by the activation of some cytokines belonging to the IL-1 cytokine family, ECM remodeling, epithelial-to-mesenchymal transition (EMT) and fibrosis. A greater comprehension of the pathophysiological consequences of GrB-mediated multiple activities may favor the design of new therapies aim to inhibit different inflammatory pathological conditions such as inflammaging and age-related diseases, EMT and organ fibrosis.

Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy

“…Granzyme B can amplify the death signal by inducing cytochrome c release. It can also activate caspase-3 directly [24].…”

“…Therefore, in these types of pathways, signaling pathways that are upstream are bypassed and execution phase of apoptosis is directly influenced. It is suggested that both the mitochondrial pathway and direct activation of caspase-3 are critical for granzyme B induced killing activates both mitochondrial pathway and caspase-3 activation [24,25]. The immune cells that express highly variable and regulated patterns of granzymes include natural killer (NK) cells, cytotoxic CD4 and CD8 T cells, and regulatory T cells (Tregs).…”

Diagnostic Tools and Biomarkers for Severe Drug Eruptions

“…Perforin makes the pore in the cell targeted membrane up to 20 nm in diameter and initiates cytotoxic molecules entering into the cytoplasm [ 44 ]. Granzyme B is a serine protease that initiates cell apoptosis in a perforin-dependent manner produced by cytotoxic cells [ 45 ]. Granzyme B cleaves and activates various caspases, such as caspases 3 and 7, which trigger cell apoptosis [ 45 ].…”

“…Granzyme B is a serine protease that initiates cell apoptosis in a perforin-dependent manner produced by cytotoxic cells [ 45 ]. Granzyme B cleaves and activates various caspases, such as caspases 3 and 7, which trigger cell apoptosis [ 45 ]. Granzyme B also has many substrates in the nucleus, leading to DNA disruption.…”

Extracellular Granzyme K Modulates Angiogenesis by Regulating Soluble VEGFR1 Release From Endothelial Cells

“…Elevated granzyme levels are also detected in the circulation in many diseases, including autoimmune diseases, atherosclerosis, pulmonary diseases, but also during infection or inflammation (15)(16)(17). Increasing evidence is emerging that granzymes exert noncytotoxic extracellular functions in inflammation, extracellular matrix degeneration, and wound healing (18)(19)(20). GrK is expressed by macrophages and plays a pathogenic role in inflammation, reepithelialization, and matrix remodeling during wound healing (21).…”