Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling

Turner, Cathy; Zeglinski, Matthew R.; Richardson, Katlyn C.; Zhao, Hongyan; Shen, Yue; Papp, Anthony; Bird, Phillip I.; Granville, David J.

doi:10.1016/j.jid.2018.09.031

Cited by 33 publications

(53 citation statements)

References 25 publications

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“…This response is observed in monocytes, human lung fibroblasts, HUVECs, human keratinocytes and skin fibroblasts ( 39 , 40 , 56 , 60 ). The release of pro-inflammatory cytokines from these cells is dependent on PAR-1 activation and downstream extracellular signal-regulated kinase 1/2 (ERK1/2) and MAPK p38 phosphorylation and independent on nuclear factor-kB (NF-kB) ( 39 , 56 , 60 ) ( Figure 1 ). HUVECs, human keratinocytes, skin fibroblasts and pulmonary fibroblasts shown an enhanced expression of IL-6 upon GrK administration, which may influence inflammation through leukocyte differentiation ( 39 , 40 , 56 ).…”

Section: Extracellular Grk Activitymentioning

confidence: 89%

“…In addition to the prior mentioned intracellular modulation of mGrK resulting in release of inflammatory cytokine IL-1b, extracellular human GrK has been reported to cause a pro-inflammatory cytokine response in vitro. This response is observed in monocytes, human lung fibroblasts, HUVECs, human keratinocytes and skin fibroblasts (39,40,56,60). The release of pro-inflammatory cytokines from these cells is dependent on PAR-1 activation and downstream extracellular signal-regulated kinase 1/2 (ERK1/2) and MAPK p38 phosphorylation and independent on nuclear factor-kB (NF-kB) (39, 56, 60) (Figure 1).…”

Section: Pro-inflammatory Cytokine Responsementioning

confidence: 95%

“…These include i) escape from the immunological synapse, ii) granzyme release post degranulation, iii) degranulation induced by chemokines or iv) cytokines and v) granzyme release following integrin-ECM proteins interaction ( 55 ). Extracellular GrK, when administered in the absence of a delivery agent such as perforin, is not considered cytotoxic in vitro ( 39 , 40 , 56 ). Furthermore, GrK, among other cell types, is expressed by CD56 bright+ NK cells, and classically activated macrophages, which either express none or negligible levels of perforin ( 21 , 56 ).…”

Section: Extracellular Grk Activitymentioning

confidence: 99%

“…Extracellular GrK, when administered in the absence of a delivery agent such as perforin, is not considered cytotoxic in vitro ( 39 , 40 , 56 ). Furthermore, GrK, among other cell types, is expressed by CD56 bright+ NK cells, and classically activated macrophages, which either express none or negligible levels of perforin ( 21 , 56 ). The presence of GrK in the extracellular space and its synthesis in the absence of perforin suggests GrK has additional functions in addition to its classically described perforin-mediated intracellular activity.…”

Section: Extracellular Grk Activitymentioning

confidence: 99%

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Intracellular and Extracellular Roles of Granzyme K

et al. 2021

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Granzymes are a family of serine proteases stored in granules inside cytotoxic cells of the immune system. Granzyme K (GrK) has been only limitedly characterized and knowledge on its molecular functions is emerging. Traditionally GrK is described as a granule-secreted, pro-apoptotic serine protease. However, accumulating evidence is redefining the functions of GrK by the discovery of novel intracellular (e.g. cytotoxicity, inhibition of viral replication) and extracellular roles (e.g. endothelial activation and modulation of a pro-inflammatory immune cytokine response). Moreover, elevated GrK levels are associated with disease, including viral and bacterial infections, airway inflammation and thermal injury. This review aims to summarize and discuss the current knowledge of i) intracellular and extracellular GrK activity, ii) cytotoxic and non-cytotoxic GrK functioning, iii) the role of GrK in disease, and iv) GrK as a potential therapeutic target.

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Section: Extracellular Grk Activitymentioning

confidence: 89%

Section: Pro-inflammatory Cytokine Responsementioning

confidence: 95%

Section: Extracellular Grk Activitymentioning

confidence: 99%

Section: Extracellular Grk Activitymentioning

confidence: 99%

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Intracellular and Extracellular Roles of Granzyme K

et al. 2021

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“…Other than secretion of growth factors [162,163], macrophages also interact with local cells such as fibroblasts to promote healing [482]. Granzyme K expressed by macrophages is elevated in burn patients, and genetic deletion of granzyme K (GzmK −/− ) in mice results in improved healing, suggesting that granzyme K activity in macrophages plays a major role in burn wound healing [483].…”

Section: Skin Immune Responses In Wound Healingmentioning

confidence: 99%

The Dynamics of the Skin’s Immune System

Nguyen

Soulika

2019

IJMS

465

339

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The skin is a complex organ that has devised numerous strategies, such as physical, chemical, and microbiological barriers, to protect the host from external insults. In addition, the skin contains an intricate network of immune cells resident to the tissue, crucial for host defense as well as tissue homeostasis. In the event of an insult, the skin-resident immune cells are crucial not only for prevention of infection but also for tissue reconstruction. Deregulation of immune responses often leads to impaired healing and poor tissue restoration and function. In this review, we will discuss the defensive components of the skin and focus on the function of skin-resident immune cells in homeostasis and their role in wound healing.

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The mRNA expression and secretion of granzyme B are up-regulated via the histamine H2 receptor in human CD4+ T cells

Dawodu,

Sand,

Nikolouli

et al. 2023

Inflamm. Res.

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Introduction Granzyme B (GZMB), a serine protease with cytotoxic and immunomodulatory functions, shows elevated levels in blood plasma of patients with atopic dermatitis (AD). It has been observed that GZMB expression in CD4+ and CD8+ T cells is higher in lesional skin in AD than in healthy skin. Since histamine is present in high concentration in the skin of AD patients, we investigated the regulation of GZMB in human CD4+ T cells by histamine. Methods Naïve CD4+ T cells polarized into Th2 cells, total CD4+ T cells treated with IL-4 for 72 h and CD4+ T cells isolated from healthy donors and AD patients were investigated. The cells were stimulated with histamine or with different histamine-receptor agonists. Gene expression was evaluated by RNA-Seq. GZMB mRNA expression was detected by quantitative real time PCR, whereas GZMB secretion was measured by ELISpot and ELISA. T cell degranulation was evaluated by flow cytometry using CD107a surface expression as a degranulation marker. Results By RNA-Seq, we identified the up-regulation of various genes of the cytotoxic pathway, in particular of GZMB, by histamine in Th2-polarized CD4+ T cells. In Th2-polarized CD4+ T cells and in CD4+ T cells activated by IL-4 the mRNA expression of GZMB was significantly up-regulated by histamine and by histamine H2 receptor (H2R) agonists. The induction of GZMB secretion by histamine was significantly higher in CD4+ T cells from AD patients than in those from healthy donors. CD107a surface expression was up-regulated by trend in response to histamine in Th2-polarized CD4+ T cells. Conclusion Our findings may help to elucidate novel mechanisms of the H2R and to achieve a better understanding of the role of GZMB in the pathogenesis of AD.

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Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling

Cited by 33 publications

References 25 publications

Intracellular and Extracellular Roles of Granzyme K

Intracellular and Extracellular Roles of Granzyme K

The Dynamics of the Skin’s Immune System

The mRNA expression and secretion of granzyme B are up-regulated via the histamine H2 receptor in human CD4+ T cells

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