Epithelial-derived gasdermin D mediates nonlytic IL-1β release during experimental colitis

Bulek, Katarzyna; Zhao, Junjie; Liao, Yun; Rana, Nitish; Corridoni, Daniele; Antanaviciute, Agne; Chen, Xing; Wang, Han; Wen, Qian; Miller-Little, William A.; Swaidani, Shadi; Tang, Fangqiang; Willard, Belinda; McCrae, Keith R.; Kang, Zizhen; Dubyak, George R.; Cominelli, Fabio; Simmons, Alison; Pizarro, Theresa T.; Li, Xiaoxia

doi:10.1172/jci138103

Cited by 96 publications

(130 citation statements)

References 85 publications

(126 reference statements)

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“…Double-gasdermin deletion further prevented release of both pro-IL-1b and mature p17 IL-1b into the supernatant, indicating dependency on GSDME, and this result was confirmed with two individual clones (Figure S3). We also noted baseline secretion of pro-IL-1b in untreated cells over the experimental time course, probably reflecting other mechanisms of GSDMD-dependent IL-1b secretion, such as the recently reported endosomal pathway (Bulek et al, 2020).…”

Section: Inflammasome Activation Triggers Apoptotic Cascade and Gsdme Cleavage In Gsdmd-deficient Macrophagessupporting

confidence: 79%

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Zhou

Abbott

2021

Cell Reports

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Section: Inflammasome Activation Triggers Apoptotic Cascade and Gsdme Cleavage In Gsdmd-deficient Macrophagessupporting

confidence: 79%

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Zhou

Abbott

2021

Cell Reports

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“…Mouse models may not always accurately mirror human disease pathogenesis, and mouse models of inflammatory diseases can be affected by small differences in experimental protocol or differences in the microbiome of mouse colonies or other poorly defined environmental or genetic differences. For example, two recent studies of dextran sodium sulfate-induced colitis found opposite results: in one study Gsdmd deficiency exacerbated colitis and enhanced cGAS–STING-mediated interferon induction 184 , while in another study lack of Gsdmd reduced disease severity 185 .…”

Section: Considerations For Therapeutic Gsdmd Inhibitionmentioning

confidence: 99%

Channelling inflammation: gasdermins in physiology and disease

Liu

Xia

Zhang

et al. 2021

Nat Rev Drug Discov

482

417

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Gasdermins were recently identified as the mediators of pyroptosis — inflammatory cell death triggered by cytosolic sensing of invasive infection and danger signals. Upon activation, gasdermins form cell membrane pores, which release pro-inflammatory cytokines and alarmins and damage the integrity of the cell membrane. Roles for gasdermins in autoimmune and inflammatory diseases, infectious diseases, deafness and cancer are emerging, revealing potential novel therapeutic avenues. Here, we review current knowledge of the family of gasdermins, focusing on their mechanisms of action and roles in normal physiology and disease. Efforts to develop drugs to modulate gasdermin activity to reduce inflammation or activate more potent immune responses are highlighted.

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“…We found an elevated level of cleaved GSDMD in goblet cells of Gpr35 f/f Vil + mice. Accordingly, GSDMD is upregulated in the colon of colitis mice and mucosal biopsies from IBD patients (Bulek et al, 2020). The same study showed that lack of GSDMD effectively reduces the severity of DSS-induced colitis (Bulek et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been linked to the pathogenesis of chronic inflammatory conditions, such as colon cancer (Derangere et al, 2014), liver fibrosis (Wree et al, 2014), and atherosclerosis (Xu et al, 2018). In this context, IBD patients and animals subjected to experimental colitis showed increased epithelial GSDMD expression and genetic ablation of GSDMD attenuated colitis severity in mice (Bulek et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Epithelial GPR35 protects fromCitrobacter rodentiuminfection by preserving goblet cells and mucosal barrier integrity

Melhem

Kaya

Kaymak

et al. 2021

Preprint

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Goblet cells are essential for maintaining intestinal health and for the defense against invasive bacterial infection. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. Here we found that epithelial Gpr35 plays a critical role in goblet cell function. Genetic deletion of Gpr35 in epithelial cells but not in from macrophages results in goblet cell depletion and dysbiosis, rendering these mice more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows how the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.

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Epithelial-derived gasdermin D mediates nonlytic IL-1β release during experimental colitis

Cited by 96 publications

References 85 publications

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases

Channelling inflammation: gasdermins in physiology and disease

Epithelial GPR35 protects fromCitrobacter rodentiuminfection by preserving goblet cells and mucosal barrier integrity

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