Intracellular immune sensing promotes inflammation via gasdermin D–driven release of a lectin alarmin

Russo, Ashley J.; Vasudevan, Swathy O.; Méndez-Huergo, Santiago P.; Kumari, Puja; Ménoret, Antoine; Duduskar, Shivalee; Wang, Chengliang; Sáez, Juan M. Pérez; Fettis, Margaret M.; Li, Chuan; Liu, Renjie; Wanchoo, Arun; Chandiran, Karthik; Ruan, Jianbin; Vanaja, Sivapriya Kailasan; Bauer, Michael; Sponholz, Christoph; Hudalla, Gregory A.; Vella, Anthony T.; Zhou, Beiyan; Deshmukh, S. D.; Rabinovich, Gabriel A.; Rathinam, Vijay

doi:10.1038/s41590-020-00844-7

Cited by 89 publications

(71 citation statements)

References 56 publications

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“…[51][52][53] On the other hand, a recent finding has shown that Gal-1 acts as a damage-associated molecular pattern and increases inflammation and lethality of sepsis. 54 Except for functioning as a secretory protein, Gal-1 located intracellularly has been associated a transformed phenotype of malignant breast cells and anti-tumor capacity of T cells, suggesting a cell-intrinsic regulation by Gal-1. 55,56 Therefore, secretory Gal-1 by ILC2 may bridge the crosstalk of ILC2 and other immune or non-immune cells in tissues.…”

Section: Discussionmentioning

confidence: 99%

Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity

Qiu

Zhang

et al. 2021

Mucosal Immunology

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Group 2 innate lymphoid cells (ILC2s) manifest tissue heterogeneity and are crucial modulators of regional immune responses. The molecular mechanisms regulating tissue ILC2 properties remain elusive. Here, we interrogate the signatures of ILC2s from five tissues at the transcriptome and epigenetic level. We have found that tissue microenvironment strongly shapes ILC2 identities. The intestine induces Aiolos+ILC2s, whereas lung and pancreas enhance Galectin-1+ILC2s. Though being a faithful gut ILC2 feature under the steady state, Aiolos is induced in non-intestinal ILC2s by pro-inflammatory cytokines. Specifically, IL-33 stimulates Aiolos expression in both human and mouse non-intestinal ILC2s. Functionally, Aiolos facilitates eosinophil recruitment by supporting IL-5 production and proliferation of ST2+ILC2s through inhibiting PD-1. At the epigenetic level, ILC2 tissue characters are imprinted by open chromatin regions (OCRs) at non-promoters. Intestinal-specific transcription factor aryl hydrocarbon receptor (Ahr) binds to Ikzf3 (encoding Aiolos) locus, increases the accessibility of an intestinal ILC2-specific OCR, and promotes the Ikzf3 transcription by enhancing H3K27ac. Consequently, Ahr prevents ILC2s entering an “exhausted-like” state through sustaining Aiolos expression. Our work elucidates mechanism of ILC2 tissue adaptation and highlights Aiolos as a potential target of type 2 inflammation.

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Section: Discussionmentioning

confidence: 99%

Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity

Qiu

Zhang

et al. 2021

Mucosal Immunology

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“…In contrast, a recent study by Russo et al. showed that S. flexneri triggers cell death exclusively through caspase-11 ( Russo et al., 2021 ). To address this dichotomy, Kobayashi et al.…”

Section: Introductionmentioning

confidence: 90%

Shigella OspC3 suppresses murine cytosolic LPS sensing

Verma

Hafeez

et al. 2021

iScience

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Summary Shigella flexneri , a cytosol-invasive gram-negative pathogen, deploys an array of type III-secreted effector proteins to evade host cell defenses. Caspase-11 and its human ortholog caspase-4 detect cytosolic lipopolysaccharide (LPS) and trigger gasdermin D-mediated pyroptosis to eliminate intra-cytoplasmic bacterial threats . However, the role of caspase-11 in combating S. flexneri is unclear. The Shigella T3SS effector OspC3 reportedly suppresses cytosolic LPS sensing by inhibiting caspase-4 but not caspase-11 activity. Surprisingly, we found that S. flexneri also uses OspC3 to inhibit murine caspase-11 activity. Mechanistically, we found that OspC3 binds only to primed caspase-11. Importantly, we demonstrate that S. flexneri employs OspC3 to prevent caspase-11-mediated pyroptosis in neutrophils, enabling bacteria to disseminate and evade clearance following intraperitoneal challenge. In contrast, S. flexneri lacking OspC3 is attenuated in a caspase-11- and gasdermin D-dependent fashion. Overall, our study reveals that OspC3 suppresses cytosolic LPS detection in a broad array of mammals.

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“…Cellular swelling is one of the features observed during pyroptosis, and hypertonic solutions have been described to rescue GSDMD-dependent cell death (61). This supports a model, in which a cell is losing its integrity and is passively rupturing due to osmotic pressure, resulting in the release of proteins such as LDH or the alarmins HMGB1 and galectin-1 (50,62). Intriguingly, a study by Kayagaki et al found that in reality, cell lysis is a process regulated by dedicated proteins (63).…”

Section: Membrane Rupturementioning

confidence: 56%

Posttranslational and Therapeutic Control of Gasdermin-Mediated Pyroptosis and Inflammation

2021

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Pyroptosis is a proinflammatory form of cell death, mediated by membrane pore-forming proteins called gasdermins. Gasdermin pores allow the release of the pro-inflammatory cytokines IL-1β and IL-18 and cause cell swelling and cell lysis leading to release of other intracellular proteins that act as alarmins to perpetuate inflammation. The best characterized, gasdermin D, forms pores via its N-terminal domain, generated after the cleavage of full length gasdermin D by caspase-1 or -11 (caspase-4/5 in humans) typically upon sensing of intracellular pathogens. Thus, gasdermins were originally thought to largely contribute to pathogen-induced inflammation. We now know that gasdermin family members can also be cleaved by other proteases, such as caspase-3, caspase-8 and granzymes, and that they contribute to sterile inflammation as well as inflammation in autoinflammatory diseases or during cancer immunotherapy. Here we briefly review how and when gasdermin pores are formed, and then focus on emerging endogenous mechanisms and therapeutic approaches that could be used to control pore formation, pyroptosis and downstream inflammation.

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Intracellular immune sensing promotes inflammation via gasdermin D–driven release of a lectin alarmin

Cited by 89 publications

References 56 publications

Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity

Tissue signals imprint Aiolos expression in ILC2s to modulate type 2 immunity

Shigella OspC3 suppresses murine cytosolic LPS sensing

Posttranslational and Therapeutic Control of Gasdermin-Mediated Pyroptosis and Inflammation

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