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Siglec-14 Enhances NLRP3-Inflammasome Activation in Macrophages
- Source :
- Journal of Innate Immunity; July 2020, Vol. 12 Issue: 4 p333-343, 11p
- Publication Year :
- 2020
-
Abstract
- Pathogenic microorganisms are sensed by the inflammasome, resulting in the release of the pro-immune and proinflammatory cytokine interleukin-1β (IL-1β). In humans, the paired <underline>s</underline>ialic acid-binding Ig-like lectin receptors Siglec-5 (inhibitory) and Siglec-14 (activating) have been shown to have reciprocal roles in regulating macrophage immune responses, but their interaction with IL-1β signaling and the inflammasome has not been characterized. Here we show that in response to known inflammasome activators (ATP, nigericin) or the sialic acid-expressing human bacterial pathogen group B Streptococcus(GBS), the presence of Siglec-14 enhances, whereas Siglec-5 reduces, inflammasome activation and macrophage IL-1β release. Human THP-1 macrophages stably transfected with Siglec-14 exhibited increased caspase-1 activation, IL-1β release and pyroptosis after GBS infection, in a manner blocked by a specific inhibitor of nucleotide-binding domain leucine-rich repeat protein 3 (NLRP3), a protein involved in inflammasome assembly. Another leading pathogen, Streptococcus pneumoniae, lacks sialic acid but rather prominently expresses a sialidase, which cleaves sialic acid from macrophages, eliminating cis- interactions with the lectin receptor, thus attenuating Siglec-14 induced IL-1β secretion. Vimentin, a cytoskeletal protein released during macrophage inflammatory activation is known to induce the inflammasome. We found that vimentin has increased interaction with Siglec-14 compared to Siglec-5, and this interaction heightened IL-1β production by Siglec-14-expressing cells. Siglec-14 is absent from some humans because of a SIGLEC5/14fusion polymorphism, and we found increased IL-1β expression in primary macrophages from SIGLEC14<superscript>+/+</superscript> individuals compared to those with the SIGLEC14<superscript>–/+</superscript> and SIGLEC14<superscript>–/–</superscript> genotypes. Collectively, our results identify a new immunoregulatory role of Siglec-14 as a positive regulator of NLRP3 inflammasome activation.
Details
- Language :
- English
- ISSN :
- 1662811X and 16628128
- Volume :
- 12
- Issue :
- 4
- Database :
- Supplemental Index
- Journal :
- Journal of Innate Immunity
- Publication Type :
- Periodical
- Accession number :
- ejs51710713
- Full Text :
- https://doi.org/10.1159/000504323