Loss of NKG2D in murine NK cells leads to increased perforin production upon long‐term stimulation with IL‐2

Prinz, Daniela; Klein, Klara R.; List, Julia; Knab, Vanessa M.; Menzl, Ingeborg; Leidenfrost, Nicoletta; Heller, Gerwin; Polić, Bojan; Putz, Eva Maria; Witalisz-Siepracka, Agnieszka; Sexl, Veronika; Gotthardt, Dagmar

doi:10.1002/eji.201948222

Cited by 10 publications

(9 citation statements)

References 45 publications

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“…They can act exogenously as secreted soluble proteins that permeabilize the plasma membrane of their target cells. This includes most pore‐forming toxins (PFTs), which are some of the most potent virulence factors found in nature (Ros & Garcia‐Saez, 2015; Dal Peraro & van der Goot, 2016) or perforin, which is released by cytotoxic T cells and Natural Killer cells (Voskoboinik et al , 2015; Prinz et al , 2020). PFPs can also be intracellular executioners as components of cell death signaling pathways (Espiritu et al , 2019; Flores‐Romero et al , 2020).…”

Section: Pore Formation In Membranes Is a Conserved Strategy To Kill mentioning

confidence: 99%

Pore formation in regulated cell death

2020

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The discovery of alternative signaling pathways that regulate cell death has revealed multiple strategies for promoting cell death with diverse consequences at the tissue and organism level. Despite the divergence in the molecular components involved, membrane permeabilization is a common theme in the execution of regulated cell death. In apoptosis, the permeabilization of the outer mitochondrial membrane by BAX and BAK releases apoptotic factors that initiate the caspase cascade and is considered the point of no return in cell death commitment. Pyroptosis and necroptosis also require the perforation of the plasma membrane at the execution step, which involves Gasdermins in pyroptosis, and MLKL in the case of necroptosis. Although BAX/BAK, Gasdermins and MLKL share certain molecular features like oligomerization, they form pores in different cellular membranes via distinct mechanisms. Here, we compare and contrast how BAX/BAK, Gasdermins, and MLKL alter membrane permeability from a structural and biophysical perspective and discuss the general principles of membrane permeabilization in the execution of regulated cell death.

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Section: Pore Formation In Membranes Is a Conserved Strategy To Kill mentioning

confidence: 99%

Pore formation in regulated cell death

2020

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“…Abundantly expressed on NK cells, NKG2D acts as a sensor for stressed cells [37]. Ligation of NKG2D by self-proteins results in the release of cytokines and the stimulation of cell-mediated cytotoxicity [38][39][40]. Interestingly, chronic exposure to NKG2D ligands results in downregulation of this receptor and, consequently, reduced NKG2D-mediated cytotoxicity [35,41].…”

Section: Discussionmentioning

confidence: 99%

NK Cell Patterns in Idiopathic Inflammatory Myopathies with Pulmonary Affection

Pawlitzki

Nelke

Rolfes

et al. 2021

Cells

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Background: Pulmonary affection (PA) is associated with a substantial increase in morbidity and mortality in patients with idiopathic inflammatory myopathies (IIM). However, the underlying immune mechanisms of PA remain enigmatic and prompt deeper immunological analyses. Importantly, the Janus-faced role of natural killer (NK) cells, capable of pro-inflammatory as well as regulatory effects, might be of interest for the pathophysiologic understanding of PA in IIM. Methods: To extend our understanding of immunological alterations in IIM patients with PA, we compared the signatures of NK cells in peripheral blood using multi-color flow cytometry in IIM patients with (n = 12, of which anti-synthetase syndrome = 8 and dermatomyositis = 4) or without PA (n = 12). Results: We did not observe any significant differences for B cells, CD4, and CD8 T cells, while total NK cell numbers in IIM patients with PA were reduced compared to non-PA patients. NK cell alterations were driven by a particular decrease of CD56dim NK cells, while CD56bright NK cells remained unchanged. Comparisons of the cell surface expression of a large panel of NK receptors revealed an increased mean fluorescence intensity of NKG2D+ on NK cells from patients with PA compared with non-PA patients, especially on the CD56dim subset. NKG2D+ and NKp46+ cell surface levels were associated with reduced vital capacity, serving as a surrogate marker for clinical severity of PA. Conclusion: Our data illustrate that PA in IIM is associated with alterations of the NK cell repertoire, suggesting a relevant contribution of NK cells in certain IIMs, which might pave the way for NK cell-targeted therapeutic approaches.

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“…IL-6 binds to the soluble IL-6 receptor glycoprotein 130 to activate JAK–STAT signaling in various cells, which, in turn, releases chemokines and promotes monocyte and neutrophil recruitment [ 44 ]. IL-2 binding to natural killer (NK) cells activates JAK 1/3, leading to augmented NK cytotoxicity [ 45 ], while IL-15 activation of JAK1 in NK cells regulates their function. Further, the differentiation and lineage amplification of CD4+ and CD8+ T cells, which play a key role in eliminating SARS-CoV-2 from infected cells, is mediated by the JAK–STAT pathway [ 46 ].…”

Section: Janus Kinases Signaling Towards Inflammation In Covid-19mentioning

confidence: 99%

Janus Kinase Signaling Pathway and Its Role in COVID-19 Inflammatory, Vascular, and Thrombotic Manifestations

Ravid

Leiva

Chitalia

2022

Cells

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Acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection continues to be a worldwide public health crisis. Among the several severe manifestations of this disease, thrombotic processes drive the catastrophic organ failure and mortality in these patients. In addition to a well-established cytokine storm associated with the disease, perturbations in platelets, endothelial cells, and the coagulation system are key in triggering systemic coagulopathy, involving both the macro- and microvasculatures of different organs. Of the several mechanisms that might contribute to dysregulation of these cells following SARS-CoV-2 infection, the current review focuses on the role of activated Janus kinase (JAK) signaling in augmenting thrombotic processes and organ dysfunction. The review concludes with presenting the current understanding and emerging controversies concerning the potential therapeutic applications of JAK inhibitors for ameliorating the inflammation-thrombosis phenotype in COVID-19 patients.

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Loss of NKG2D in murine NK cells leads to increased perforin production upon long‐term stimulation with IL‐2

Cited by 10 publications

References 45 publications

Pore formation in regulated cell death

Pore formation in regulated cell death

NK Cell Patterns in Idiopathic Inflammatory Myopathies with Pulmonary Affection

Janus Kinase Signaling Pathway and Its Role in COVID-19 Inflammatory, Vascular, and Thrombotic Manifestations

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