Granzyme B as a therapeutic target: an update in 2022

Aubert, Alexandre; Lane, Michael; Jung, Karen; Granville, David J.

doi:10.1080/14728222.2022.2161890

Cited by 8 publications

(8 citation statements)

References 118 publications

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“…Similarly, granzyme B is a serine protease released by cytotoxic T cells and natural killer cells and is highly upregulated in brain-infiltrating lymphocytes during flavivirus encephalitis (13,(51)(52)(53). In addition to its role in degrading BBB components, granzyme B is a significant source of immunopathology due its intrinsic neurotoxic activity (54)(55)(56)(57). These activities highlight the need for tight regulation of inflammatory protease activity to balance effective antiviral immune responses with the preservation of CNS homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Astrocytic RIPK3 exerts protective anti-inflammatory activity during viral encephalitis via induction of serpin protease inhibitors

Lindman,

Estevez,

Marmut

et al. 2024

Preprint

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Flaviviruses pose a significant threat to public health due to their ability to infect the central nervous system (CNS) and cause severe neurologic disease. Astrocytes play a crucial role in the pathogenesis of flavivirus encephalitis through their maintenance of blood-brain barrier (BBB) integrity and their modulation of immune cell recruitment and activation within the CNS. We have previously shown that receptor interacting protein kinase-3 (RIPK3) is a central coordinator of neuroinflammation during CNS viral infection, a function that occurs independently of its canonical function in inducing necroptotic cell death. To date, however, roles for necroptosis-independent RIPK3 signaling in astrocytes are poorly understood. Here, we use mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an unexpected anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes was required for host survival in multiple models of flavivirus encephalitis, where it restricted neuropathogenesis by limiting immune cell recruitment to the CNS. Transcriptomic analysis revealed that, despite inducing a traditional pro-inflammatory transcriptional program, astrocytic RIPK3 paradoxically promoted neuroprotection through the upregulation of serpins, endogenous protease inhibitors with broad immunomodulatory activity. Notably, intracerebroventricular administration of SerpinA3N in infected mice preserved BBB integrity, reduced leukocyte infiltration, and improved survival outcomes in mice lacking astrocytic RIPK3. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation and suggests new therapeutic targets for the treatment of flavivirus encephalitis.

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Section: Discussionmentioning

confidence: 99%

Astrocytic RIPK3 exerts protective anti-inflammatory activity during viral encephalitis via induction of serpin protease inhibitors

Lindman,

Estevez,

Marmut

et al. 2024

Preprint

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“…[24] Granzyme B, which is produced by a wide variety of cells, especially T lymphocytes and natural killer cells, plays different roles; one of the well-known ones is key functions in cell apoptosis. [43,44] Figure 1 schematically presents certain consequences of protease activities relevant to the wound-healing process.…”

Section: Proteases Their Origins and Functionsmentioning

confidence: 99%

“…The Figure 1. A schematic illustration of some results of proteases' activity: proteases are involved in wound contraction, [35] angiogenesis, [39] attraction of the neutrophils to the inflammation site from the blood vessels, [37] hydrolysis of cells' junctions, [24] resorption of provisional matrix, [38] cell differentiation, [41] apoptosis, [43] proliferation, [41] and migration. [32] literature on how protease levels may differ between chronic and acute wounds and how factors such as bacterial infection or age can affect them will be reviewed in the next section.…”

Section: Proteases Their Origins and Functionsmentioning

confidence: 99%

“…They observed that suppression of granzyme B expression was associated with improved wound healing. Aubert et al, in a review paper published in 2022, [43] stated that the build-up of the granzyme B in the skin hampers the wound healing process; more details pertinent to this particular protease can be found in that review article and its earlier version. [130] Izzo and colleagues observed a correlation between the failure of skin grafts and wounds' MMP activity.…”

Section: Potential Detrimental Effects Of Excessive Proteolytic Activitymentioning

confidence: 99%

“…A schematic illustration of some results of proteases’ activity: proteases are involved in wound contraction, [ 35 ] angiogenesis, [ 39 ] attraction of the neutrophils to the inflammation site from the blood vessels, [ 37 ] hydrolysis of cells’ junctions, [ 24 ] resorption of provisional matrix, [ 38 ] cell differentiation, [ 41 ] apoptosis, [ 43 ] proliferation, [ 41 ] and migration. [ 32 ] …”

Section: Proteases Their Origins and Functionsmentioning

confidence: 99%

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Approaches to Control and Monitor Protease Levels in Chronic Wounds

Kolahreez,

Ghasemi‐Mobarakeh,

Liebner

et al. 2024

Advanced Therapeutics

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Some wounds do not follow the typical healing trajectory and show very little, if any, progress. They dreadfully threaten the patients' quality of life and may even lead to limb amputation and death. Several interrelated systemic and local factors may cause a delay in wound healing. The microenvironment of these wounds could be different from wounds that heal spontaneously or with standard treatment. As discussed in the present work, proteases’ levels or activity could be elevated in some cases of chronic ulcers; infection could aggravate the situation. A detailed overview of the proteases’ effect on wound healing is presented in this paper. Assuming untimely or irregularly excessive proteolytic activity plays a pathological role, some researchers targeted attenuation of protease level as a strategy to promote healing. This could be done via different approaches, including physical removal, inhibiting their activity, and controlling their expression directly through gene silencing or indirectly, for instance, by resolving infection. Apart from targeting protease modulation as a therapeutic strategy, many studies have examined the protease state to gain insights into the underlying mechanisms by which a remedy, dressing, or specific therapy has affected the healing process. This article aims to provide an overview of the studies in these two categories. Of course, various proteases are involved in the healing process, but in each study, usually, only one or some of them were investigated; matrix metalloproteinase‐2 (MMP‐2), MMP‐9, and human neutrophil elastase (HNE) are among them. Furthermore, in some cases, cumulative proteolytic activity has been evaluated in terms of gelatinolytic, collagenolytic, or caseinolytic activity, which is also absolutely beneficial. Some research groups have considered the potential of proteases as a diagnostic or prognostic biomarker and have tried to develop some sensors or indicators; this topic has also been covered in the present work.This article is protected by copyright. All rights reserved

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