GP191 Dysregulation of the inflammasome in children with down syndrome. (June 2019)

• Record Type: Journal Article
• Authors: Worrall, Amy P; Gallagher, Eleanor; Huggard, Dean; Kelly, Lynne; Molloy, Eleanor
• Is Part Of: Archives of disease in childhood. Volume 104:(2019)Supplement 3
• Page Start: A108
• Page End: A108
• Publication Date: 2019-06
• Subjects: Children -- Diseases -- Periodicals; Infants -- Diseases -- Periodicals; 618.920005
• DOI: 10.1136/archdischild-2019-epa.252
• Languages: English
• ISSNs: 0003-9888

Abstract

Abstract : Aims: Children with Down Syndrome (DS) are at an increased risk of infection and sepsis, and other inflammatory conditions such as arthritis. Various forms of immune dysregulation have been documented in DS including lymphopaenia, altered serum cytokines, reduced response to vaccinations as well as leukaemias. The NLRP3 (NLR family pyrin domain containing 3) inflammasome is a multiprotein complex that generates pro-inflammatory cytokines as part of the innate immune response to infection andis implicated in several inflammatory disorders. NLRP3 is also an important target for anti-inflammatory therapies. We aimed to characterize gene expression of the NLRP3 inflammasome in children with DS. Methods: Peripheral venous whole blood samples were collected from children with DS (n=18) and healthy age-matched paediatric controls (n=10). Whole blood samples were treated with lipopolysaccharide (LPS), melatonin or both. Whole blood RNA was isolated, cDNA was synthesized and analysed by quantitative PCR for expression of NLRP3, ASC (Apoptosis-associated speck like protein containing a caspase recruitment domain) and IL-1β (Interleukin-1-β). Statistical analysis was performed using ANOVA and t-test with Graphpad Prism Version 7.0. Results: The expression of NLRP3 and IL-1β was similar between children with DS and controls at baseline. ASC was significantly reduced in children with DS ( p= 0.0003 ). Both cohorts demonstrated a significant rise in the expression of IL-1β following treatment with LPS ( p≤ 0.0001 ). Melatonin significantly attenuated IL-1β expression in children with DS, this was not demonstrated for the control group ( p≤ 0.0001 ). Conclusion: Dysfunction of various elements of the inflammasome and its associated regulatory genes could be responsible for increased susceptibility to infection in children with DS. Melatonin significantly reduces IL-1β expression following LPS and may be beneficial as an adjunctive therapy in children with DS.