1. Siglec-14 Enhances NLRP3-Inflammasome Activation in Macrophages
- Author
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Tsai, Chih-Ming, Riestra, Angelica M, Ali, Syed Raza, Fong, Jerry J, Liu, Janet Z, Hughes, Gillian, Varki, Ajit, and Nizet, Victor
- Subjects
Biodefense ,Vaccine Related ,Emerging Infectious Diseases ,Prevention ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Infection ,Humans ,Inflammasomes ,Lectins ,Macrophages ,NLR Family ,Pyrin Domain-Containing 3 Protein ,Receptors ,Cell Surface ,Streptococcal Infections ,Streptococcus agalactiae ,THP-1 Cells ,Siglec ,Interleukin-1 beta ,Caspase-1 ,Inflammasome ,Innate immunity ,Vimentin ,Interleukin-1β ,Medical and Health Sciences - 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 sialic 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 SIGLEC5/14 fusion polymorphism, and we found increased IL-1β expression in primary macrophages from SIGLEC14+/+ individuals compared to those with the SIGLEC14-/+ and SIGLEC14-/- genotypes. Collectively, our results identify a new immunoregulatory role of Siglec-14 as a positive regulator of NLRP3 inflammasome activation.
- Published
- 2020