Pyroptosis in host defence against bacterial infection

Brokatzky, Dominik; Mostowy, Serge

doi:10.1242/dmm.049414

Cited by 35 publications

(17 citation statements)

References 142 publications

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“…Early recognition and treatment of sepsis and its associated encephalopathy is critical for reducing the risk of long-term neurological complications and improving the outcomes [ 8 ]. Pyroptosis is a type of programmed cell death that is associated with inflammation and is triggered by the activation of certain signaling pathways in response to certain stimuli, including bacterial and viral infections, as well as cellular stress [ 9 , 10 , 11 , 12 , 13 ]. Gasdermin D (GSDMD) is known to regulate pyroptosis through its interaction with caspase-1, a critical enzyme involved in inflammasome activation.…”

Section: Introductionmentioning

confidence: 99%

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Xie

Bai

et al. 2023

Brain Sciences

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Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, which is a life-threatening condition resulting from a dysregulated host response to infection. Pyroptosis, a pro-inflammatory mode of lytic cell death mediated by GSDMD (Gasdermin D), is involved in the pathogenesis of SAE. While autophagy has been extensively studied in SAE, the role of nuclear autophagy is not yet well understood. In this study, we aimed to investigate the involvement of pyroptosis and neural nuclear autophagy in the pathogenesis of SAE. We analyzed a CLP (cecal ligation and puncture)-induced SAE model in wild-type and GSDMD−/− mice to gain insights into the underlying mechanisms. Here, we show that in sepsis, neural nuclear autophagy is extremely activated, and nuclear LaminB decreases and is accompanied by an increase in the ratio of LC3BII/I. These effects can be reversed in GSDMD−/− mice. The behavioral outcomes of septic wild-type mice are impaired by the evidence from the novel object recognition test (NORT) and open field test (OFT), but are improved in septic GSDMD−/− mice. In conclusion, our study demonstrates the activation of neural nuclear autophagy in SAE. The absence of GSDMD inhibits nuclear autophagy and improves the behavioral outcomes of SAE.

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Section: Introductionmentioning

confidence: 99%

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Xie

Bai

et al. 2023

Brain Sciences

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“…Indeed, even if pyroptosis functions as potential mechanism to eliminate incipient neoplastic cells, the resulting inflammatory response may counterintuitively create a pro-tumorigenic niche that favors oncogenic transformation (23). Relatedly, pyroptosis has perhaps been most often studied in the context of host immune response against infections (57)(58)(59)(60). The role of pyroptosis in cancer is less well understood, although evidence for pyroptosis playing a tumor suppressive role is accumulating in melanomas and breast cancers (61)(62)(63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells

Hom

Sun

Campbell

et al. 2023

Preprint

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In normal tissue homeostasis, bidirectional communication between different cell types can shape numerous biological outcomes. Many studies have documented instances of reciprocal communication between fibroblasts and cancer cells that functionally change cancer cell behavior. However, less is known about how these heterotypic interactions shape epithelial cell function in the absence of oncogenic transformation. Furthermore, fibroblasts are prone to undergo senescence, which is typified by an irreversible cell cycle arrest. Senescent fibroblasts are also known to secrete various cytokines into the extracellular space; a phenomenon that is termed the senescence-associated secretory phenotype (SASP). While the role of fibroblast derived SASP factors on cancer cells has been well studied, the impact of these factors on normal epithelial cells remains poorly understood. We discovered that treatment of normal mammary epithelial cells with conditioned media (CM) from senescent fibroblasts (SASP CM) results in a caspase-dependent cell death. This capacity of SASP CM to cause cell death is maintained across multiple senescence-inducing stimuli. However, the activation of oncogenic signaling in mammary epithelial cells mitigates the ability of SASP CM to induce cell death. Despite the reliance of this cell death on caspase activation, we discovered that SASP CM does not cause cell death by the extrinsic or intrinsic apoptotic pathway. Instead, these cells die by an NLRP3, caspase-1, and gasdermin D (GSDMD)-dependent induction of pyroptosis. Taken together, our findings reveal that senescent fibroblasts can cause pyroptosis in neighboring mammary epithelial cells, which has implications for therapeutic strategies that perturb the behavior of senescent cells.

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“…Our results also show that Sept6 and Sept15 are required for host defence against S. flexneri infection. Although septins have previously been implicated in cell-autonomous immunity and cell death (Brokatzky & Mostowy, 2022;Mostowy & Cossart, 2012;Mostowy & Shenoy, 2015), the precise role of Sept6 and Sept15 in host defence in vivo is not known.…”

Section: Discussionmentioning

confidence: 99%

Zebrafish null mutants of Sept6 and Sept15 are viable but more susceptible to Shigella infection

et al. 2023

Self Cite

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Septins are evolutionarily conserved GTP‐binding proteins known for their roles in cell division and host defence against Shigella infection. Although septin group members are viewed to function as hetero‐oligomeric complexes, the role of individual septins within these complexes or in isolation is poorly understood. Decades of work using mouse models has shown that some septins (including SEPT7) are essential for animal development, while others (including SEPT6) are dispensable, suggesting that some septins may compensate for the absence of others. The zebrafish genome encodes 19 septin genes, representing the full complement of septin groups described in mice and humans. In this report, we characterise null mutants for zebrafish Sept6 (a member of the SEPT6 group) and Sept15 (a member of the SEPT7 group) and test their role in zebrafish development and host defence against Shigella infection. We show that null mutants for Sept6 and Sept15 are both viable, and that expression of other zebrafish septins are not significantly affected by their mutation. Consistent with previous reports using knockdown of Sept2, Sept7b, and Sept15, we show that Sept6 and Sept15 are required for host defence against Shigella infection. These results highlight Shigella infection of zebrafish as a powerful system to study the role of individual septins in vivo.

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Pyroptosis in host defence against bacterial infection

Cited by 35 publications

References 142 publications

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

A role for fibroblast-derived SASP factors in the activation of pyroptotic cell death in mammary epithelial cells

Zebrafish null mutants of Sept6 and Sept15 are viable but more susceptible to Shigella infection

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