The Multifaceted Function of Granzymes in Sepsis: Some Facts and a Lot to Discover.

Marcela Garzón-Tituaña,Julián Pardo,José R Paño-Pardo,Elena Morte-Romea,José L Sierra-Monzón,Ariel Ramirez-Labrada,Luis Martinez-Lostao,Llipsy Santiago,Maykel A Arias,Eva M Galvez

doi:10.3389/fimmu.2020.01054

Abstract

Sepsis is a serious global health problem. In addition to a high incidence, this syndrome has a high mortality and is responsible for huge health expenditure. The pathophysiology of sepsis is very complex and it is not well-understood yet. However, it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy, increasing the risk of secondary infections. Granzymes (Gzms) are a family of serine proteases classified according to their cleavage specificity. Traditionally, it was assumed that all Gzms acted as cytotoxic proteases. However, recent evidence suggests that GzmB is the one with the greatest cytotoxic capacity, while the cytotoxicity of others such as GzmA and GzmK is not clear. Recent studies have found that GzmA, GzmB, GzmK, and GzmM act as pro-inflammatory mediators. Specially, solid evidences show that GzmA and GzmK function as extracellular proteases that regulate the inflammatory response irrespectively of its ability to induce cell death. Indeed, studies in animal models indicate that GzmA is involved in the cytokine release syndrome characteristic of sepsis. Moreover, the GZM family also could regulate other biological processes involved in sepsis pathophysiology like the coagulation cascade, platelet function, endothelial barrier permeability, and, in addition, could be involved in the immunosuppressive stage of sepsis. In this review, we provide a comprehensive overview on the contribution of these novel functions of Gzms to sepsis and the new therapeutic opportunities emerging from targeting these proteases for the treatment of this serious health problem.

Highlights

The immune system is the most important line of defense against pathogens
The immune response to infection is initiated after the recognition of pathogen derived molecules known as Pathogen Associated Molecular Patterns (PAMPs) by specific receptors known as PAMP receptors
Simultaneous and interrelated inflammatory and anti-inflammatory responses are developed [3, 4], it is widely accepted that the initial phase of sepsis is characterized by a hyperinflammatory response while the late phase is characterized by immunosuppression and immune anergy that increases the risk of other opportunistic infections, specially bacterial and fungal

Summary

Introduction

The immune system is the most important line of defense against pathogens. The immune response to infection is initiated after the recognition of pathogen derived molecules known as Pathogen Associated Molecular Patterns (PAMPs) by specific receptors known as PAMP receptors. It has been shown that extracellular GzmA is able to induce the production of different inflammatory cytokines such as IL1β, TNF-α IL-6, or IL-8 in both mouse and human cells like monocytes, macrophages, fibroblasts, endothelial and epithelial cells [17, 20] (Table 1) which might contribute to the cytokine storm observed during sepsis.

Results

Conclusion