Oxylipins and metabolites from pyroptotic cells act as promoters of tissue repair
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1093474 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28503260_1.fastq.gz | Fastqsanger.gz | |||
| SRR28503260_2.fastq.gz | Fastqsanger.gz | |||
| SRR28503261_1.fastq.gz | Fastqsanger.gz | |||
| SRR28503261_2.fastq.gz | Fastqsanger.gz | |||
| SRR28503262_1.fastq.gz | Fastqsanger.gz |
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Project description:Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin 1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system where macrophages are induced to undergo pyroptosis without IL-1β/⍺ release (denoted Pyro-1), we uncover unexpected beneficial effects of the Pyro-1 secretome. First, we noted that the Pyro-1 supernatants upregulated gene signatures linked to migration, cellular proliferation, and wound healing. Consistent with this gene signature, Pyro-1 supernatants boosted migration of primary fibroblasts and macrophages, as well as faster wound closure in vitro, and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro-1 supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound healing effects. Focusing specifically on the oxylipin prostaglandin E2 (PGE2), we find that PGE2 synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation, and COX2 activity; further, PGE2 synthesis occurs late in pyroptosis, with its release dependent on Gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301+ macrophages. Collectively, these data advance the concept that the pyroptotic secretome 1 Mehrotra et al., Page No. possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.
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Project description:Oxylipins play a role in the response of plants to pathogens both as antimicrobial compounds and as signaling molecules. In potato, pathogen infection leads to the stimulation of the 9-lipoxygenase pathway (Göbel et al. 2001; 2002; Stumpe et al. 2001). In order to analyze whether 9-LOX-derived oxylipins such as colnele(n)ic acid (products of the 9-divinyl ether synthase reaction) act as signaling molecules for the activation of defense responses, transgenic potato plants (Solanum tuberosum cv. Désirée) were generated which express an RNAi construct directed against the pathogen-induced 9-lipoxygenase (Göbel et al. 2003) or against the pathogen-induced 9-divinyl ether synthase (Stumpe et al. 2001). Highly reduced transcript levels correlate with low levels of 9-lipoxygenase-derived oxylipins (Göbel et al. 2003). Transgenic and wild type plants were grown as sterile plants on MS medium supplemented with agar in a phytochamber with 16 h of light [200 µE] at 22 °C. After transfer to soil, plants were kept in a phytochamber with 16 h of light [200 µE], 18 °C and 60 % humidity for four weeks. Lower leaves were infiltrated with a suspension of Pseudomonas syringae pv. maculicola at a concentration of 108 cfu/ml MgCl2 or, as a control, 10 mM MgCl2-solution. RNA was isolated both from the infiltrated leaves and the upper, non-treated leaves using the trizol method. Subsequently, RNA was digested with DNase and purified via Qiagen RNeasy Kit (Qiagen, Hilden, Germany) according to the manufacturer´s instructions. Keywords: Direct comparison
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