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

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.

CXCL11 Correlates With Antitumor Immunity and an Improved Prognosis in Colon Cancer

“…We found that CXCL11 was positively correlated with CCL4, CCL5, CXCL9, and CXCL10 in COAD, which are associated with DC, NK, and T cell recruitment and play important roles in inhibiting tumor growth and improving prognosis ( Böttcher et al, 2018 ; Cabrero-de, Las Heras and Martínez-Balibrea, 2018 ). Accordingly, we found positive correlations between CXCL11 and cytotoxic genes (IFNG, GZMA, GZMB, GZMK, and GZMM), which were validated to enhance the cytotoxic function by other immunocytes and contribute to the immunostimulatory microenvironment ( Garzón-Tituaña et al, 2020 ). These data indicate that CXCL11 promotes antitumor immunity by mediating the infiltration of immunocytes.…”

Epigenetic scores for the circulating proteome as tools for disease prediction

“…Nevertheless, even where DNAm proxies CRP and IL6 correlate ~0.2 with measured protein levels, they provide a more stable measure of expression than proteomic measures when averaged longitudinally; they often outperform the measured proteins in relation to associations with health outcomes and lifestyle factors [13][14][15] . As with CRP and IL6, many of the proteins we have created proxies for are involved in or associated with the acute-phase response; GZMA is thought to promote the release of IL6, IL8 and TNF-alpha, thereby inducing a cytokine syndrome in those with sepsis (a condition hallmarked by a rapid alterations in the inflammatory state) 11,54 .…”

Intracellular expression of granzymes A, B, K and M in blood lymphocyte subsets of critically ill patients with or without sepsis

“…Earlier studies have indicated the involvement of Gzm in the pathophysiology of sepsis ( 35 ). GzmA, B, K and M can stimulate the production, release and/or processing of several cytokines ( 6 ).…”