Human polymorphisms in GSDMD alter the inflammatory response

Exomic studies have demonstrated that innate immune genes exhibit an even higher degree of variation than the majority of other gene families. However, the phenotypic implications of this genetic variation are not well understood, with effects ranging from hypomorphic to silent to hyperfunctioning. In this work, we study the functional consequences of this variation by investigating polymorphisms in gasdermin D, the key pyroptotic effector protein. We find that, although SNPs affecting potential posttranslational modifications did not affect gasdermin D function or pyroptosis, polymorphisms disrupting sites predicted to be structurally important dramatically alter gasdermin D function. The manner in which these polymorphisms alter function varies from conserving normal pyroptotic function to inhibiting caspase cleavage to disrupting oligomerization and pore formation. Further, downstream of inflammasome activation, polymorphisms that cause loss of gasdermin D function convert inflammatory pyroptotic cell death into immunologically silent apoptotic cell death. These findings suggest that human genetic variation can alter mechanisms of cell death in inflammation.

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Dapagliflozin Alleviates Renal Fibrosis by Inhibiting RIP1-RIP3-MLKL-Mediated Necroinflammation in Unilateral Ureteral Obstruction

Frontiers in Pharmacology ◽

10.3389/fphar.2021.798381 ◽

2022 ◽

Vol 12 ◽

Author(s):

Mei Ying Xuan ◽

Shang Guo Piao ◽

Jun Ding ◽

Qi Yan Nan ◽

Mei Hua Piao ◽

...

Keyword(s):

Cell Death ◽

Ureteral Obstruction ◽

Renal Fibrosis ◽

Apoptotic Cell ◽

Subsequent Development ◽

Unilateral Ureteral Obstruction ◽

Apoptotic Cell Death ◽

Inflammasome Activation ◽

Renal Tubular

Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, offers renoprotection in diabetes. However, potential for use in nondiabetic kidney disease remains unknown. Herein, we assessed whether dapagliflozin alleviates renal fibrosis by interfering with necroinflammation in a rat model of unilateral ureteral obstruction (UUO) and in vitro. After induction of UUO, rats were administered dapagliflozin daily for seven consecutive days. UUO induced significant renal tubular necrosis and overexpression of RIP1-RIP3-MLKL axis proteins; these coincided with NLRP3 inflammasome activation, and subsequent development of renal fibrosis. Oxidative stress caused by UUO is tightly associated with endoplasmic reticulum stress and mitochondrial dysfunction, leading to apoptotic cell death through Wnt3α/β-catenin/GSK-3β signaling; all of which were abolished by both dapagliflozin and specific RIP inhibitors (necrostatin-1 and GSK872). In H2O2-treated HK-2 cells, dapagliflozin and RIP inhibitors suppressed overexpression of RIP1-RIP3-MLKL proteins and pyroptosis-related cytokines, decreased intracellular reactive oxygen species production and apoptotic cell death, whereas cell viability was improved. Moreover, activated Wnt3α/β-catenin/GSK-3β signaling was inhibited by dapagliflozin and Wnt/β-catenin inhibitor ICG-001. Our findings suggest that dapagliflozin ameliorates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in UUO.

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Masterminds or minions? Cysteine proteinases in plant programmed cell deathThis review is one of a selection of papers published in the Special Issue on Plant Cell Biology.

Canadian Journal of Botany ◽

10.1139/b06-038 ◽

2006 ◽

Vol 84 (4) ◽

pp. 651-667 ◽

Cited By ~ 15

Author(s):

Christopher P. Trobacher ◽

Adriano Senatore ◽

John S. Greenwood

Keyword(s):

Cell Death ◽

Cell Biology ◽

Apoptotic Cell ◽

Gene Families ◽

Cysteine Proteinases ◽

Special Issue ◽

Multicellular Organisms ◽

Protease Expression ◽

Signalling Cascade ◽

Selection Of

Cysteine proteinases are ubiquitously involved in programmed cell death (PCD) in multicellular organisms. In animals, one group of cysteine proteinases, the cysteine-dependent aspartate-specific proteinases (caspases), are involved in a proteolytic signalling cascade that controls apoptosis, the most studied form of PCD. The enzymes act as both masterminds and executioners in apoptotic cell death. In plants, members of the metacaspase family, as well as those of the papain-like and legumain families, of cysteine proteinases have all been implicated in PCD. These enzymes often belong to sizeable gene families, with Arabidopsis having 9 metacaspase, 32 papain-like, and 4 legumain genes. This redundancy has made it difficult to ascertain the functional importance of any particular enzyme in plant PCD, as many are often expressed in a given tissue undergoing PCD. As yet, mechanisms similar to the apoptotic caspase cascade in animals have not been uncovered in plants and, indeed, may not exist. Are the various cysteine proteinases, so often implicated in plant PCD, merely acting as minions in the process? This review will outline reports of cysteine proteinases associated with plant PCD, discuss problems in determining the function of specific proteases, and suggest avenues for determining how these enzymes might be regulated and how PCD pathways upstream of protease expression and activation might operate.

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Genetic Variation of Innate Immune Genes in HIV-Infected African Patients With or Without Oropharyngeal Candidiasis

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0b013e3181e53c64 ◽

2010 ◽

Vol 55 (1) ◽

pp. 87-94 ◽

Cited By ~ 29

Author(s):

Theo S Plantinga ◽

Omar J M Hamza ◽

Janet A Willment ◽

Bart Ferwerda ◽

Nicole M D van de Geer ◽

...

Keyword(s):

Genetic Variation ◽

Innate Immune ◽

Oropharyngeal Candidiasis ◽

Immune Genes ◽

Innate Immune Genes ◽

African Patients

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Apoptotic cell death: the caspase-cleavage “gold rush”

The Lancet ◽

10.1016/s0140-6736(05)61009-4 ◽

2005 ◽

Vol 365 (9467) ◽

pp. 1293-1294 ◽

Cited By ~ 3

Author(s):

GR Foster

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Gold Rush ◽

Apoptotic Cell Death ◽

Caspase Cleavage

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Apoptosis signalling pathways in seizure-induced neuronal death and epilepsy

Biochemical Society Transactions ◽

10.1042/bst0350421 ◽

2007 ◽

Vol 35 (2) ◽

pp. 421-423 ◽

Cited By ~ 52

Author(s):

D.C. Henshall

Keyword(s):

Cell Death ◽

Neuronal Death ◽

Calcium Release ◽

Apoptotic Cell ◽

Death Receptor ◽

Gene Families ◽

Signalling Pathways ◽

Intrinsic Pathway ◽

Extrinsic Pathway ◽

Cell Death Pathways

Delineating the molecular pathways underlying seizure-induced neuronal death may yield novel strategies for brain protection against prolonged or repetitive seizures. Glutamate-mediated excitotoxicity and necrosis is a primary contributing mechanism but seizures also activate programmed (apoptotic) cell death pathways. Apoptosis signalling pathways are typically initiated following perturbation of intracellular organelle function (intrinsic pathway) or by activated cell-surface-expressed death receptors (extrinsic pathway), with signalling cascades orchestrated in part by the Bcl-2 and caspase gene families. In this review, evidence for these pathways from experimental seizure modelling and clinical material from patients with intractable temporal lobe epilepsy is examined. Seizures cause mitochondrial dysfunction and activate intrinsic pathway components including pro-apoptotic Bcl-2 family proteins and caspases, processes that may be partly calcium-induced. The ER (endoplasmic reticulum) has emerged as a major intrinsic pathway trigger for apoptosis and its function may also be compromised following seizures and in epilepsy. The extrinsic, death-receptor-dependent pathway is also rapidly engaged following experimental seizures and in patient brain, supporting a previously unexpected apical role for a calcium-independent pathway. When considered alongside emerging functions of apoptosis-regulatory proteins in non-cell-death processes, including regulating intracellular calcium release and neuronal (re)structuring, apoptosis signalling pathways can be viewed as an important developing focus of research into how to obviate the deleterious impact of seizures on the brain.

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Palmitate induces apoptotic cell death and inflammasome activation in human placental macrophages

10.1101/799718 ◽

2019 ◽

Author(s):

Lisa M. Rogers ◽

Carlos H. Serezani ◽

Alison J. Eastman ◽

Alyssa H. Hasty ◽

Linda Englund-Ögge ◽

...

Keyword(s):

Cell Death ◽

Metabolic Diseases ◽

Apoptotic Cell ◽

Interleukin 1 ◽

Metabolic Stress ◽

Apoptotic Cell Death ◽

Inflammasome Activation ◽

Placental Macrophages ◽

The Impact ◽

Placental Macrophage

AbstractIntroductionThere is an increasing prevalence of non-communicable diseases worldwide. Metabolic diseases such as obesity and gestational diabetes mellitus (GDM) increasingly affect women during pregnancy, which can harm pregnancy outcomes and the long-term health and wellbeing of exposed offspring. Both obesity and GDM have been associated with proinflammatory effects within the placenta, the critical organ governing fetal development.MethodsThe purpose of these studies was to model, in vitro, the effects of metabolic stress (high levels of glucose, insulin and saturated lipids) on placental macrophage biology, since these cells are the primary innate immune phagocyte within the placenta with roles in governing maternofetal immune tolerance and antimicrobial host defense. Macrophages were isolated from the villous core of term, human placentae delivered through nonlaboring, elective Cesarean sections and exposed to combinations of elevated glucose (30 mM), insulin (10 nM) and the saturated lipid palmitic acid (palmitate, 0.4 mM).ResultsWe found that palmitate alone induced the activation of the nucleotide-binding oligomerization domain-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in placental macrophages, which was associated with increased interleukin 1 beta release and an increase in apoptotic cell death. Glucose and insulin neither provoked these effects nor augmented the impact of palmitate itself.DiscussionOur findings confirm an impact of saturated fat on placental macrophage immune activation and could be relevant to the impact of metabolic stress in vivo.

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Phagocytic clearance of apoptotic, necrotic, necroptotic and pyroptotic cells

Biochemical Society Transactions ◽

10.1042/bst20200696 ◽

2021 ◽

Author(s):

Georgia K. Atkin-Smith

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Cell Types ◽

Rapid Expansion ◽

Apoptotic Cell Clearance ◽

Cell Clearance ◽

Functional Consequences ◽

Dying Cells ◽

Cell Engulfment

Although millions of cells in the human body will undergo programmed cell death each day, dying cells are rarely detected under homeostatic settings in vivo. The swift removal of dying cells is due to the rapid recruitment of phagocytes to the site of cell death which then recognise and engulf the dying cell. Apoptotic cell clearance — the engulfment of apoptotic cells by phagocytes — is a well-defined process governed by a series of molecular factors including ‘find-me’, ‘eat-me’, ‘don't eat-me’ and ‘good-bye’ signals. However, in recent years with the rapid expansion of the cell death field, the removal of other necrotic-like cell types has drawn much attention. Depending on the type of death, dying cells employ different mechanisms to facilitate engulfment and elicit varying functional impacts on the phagocyte, from wound healing responses to inflammatory cytokine secretion. Nevertheless, despite the mechanism of death, the clearance of dying cells is a fundamental process required to prevent the uncontrolled release of pro-inflammatory mediators and inflammatory disease. This mini-review summarises the current understandings of: (i) apoptotic, necrotic, necroptotic and pyroptotic cell clearance; (ii) the functional consequences of dying cell engulfment and; (iii) the outstanding questions in the field.

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