Melatonin As an Immunomodulator in Children with Down Syndrome

Overview

Journal Pediatr Res

Specialties Biology
Pediatrics

Date 2021 Aug 17

PMID 34400791

Citations 3

Authors

Dean Huggard

Lynne Kelly

Amy Worrall

Eleanor Gallagher

Lida Fallah

Lucas Lu Yoo

Fiona McGrane

Niamh Lagan

Edna Roche

Joanne Balfe

Derek G Doherty

Eleanor J Molloy

Affiliations

Soon will be listed here.

Abstract

Background: Down syndrome (DS) is a disorder characterised by marked immune dysfunction, increased mortality from sepsis, chronic inflammation, increased oxidative stress, sleep disturbance and possibly abnormal endogenous melatonin levels. Melatonin has a myriad of immune functions, and we hypothesised that this therapeutic agent could modulate the innate immune system in this cohort.

Methods: We investigated neutrophil and monocyte function (CD11b, TLR4 expression by flow cytometry), genes involved in TLR signalling (MyD88, IRAK4, TRIF), the inflammasome (NLRP3, IL-1β), and circadian rhythm (BMAL, CLOCK, CRY) by qPCR, and inflammatory cytokines (IL-2, IL-6, IL-8, IL-18, IL-1β, TNF-α, IFN-γ, IL-10, IL-1ra, VEGF, Epo, GM-CSF) by enzyme-linked immunosorbent assay (ELISA) following immunomodulation with LPS endotoxin and melatonin. 47 children with DS and 23 age- and sex-matched controls were recruited.

Results: We demonstrated that melatonin has several significant effects by reducing CD11b and TLR4 expression, attenuating TLR signalling, genes involved in the inflammasome and has the potential to reduce LPS-induced inflammatory responses.

Conclusions: Immunomodulatory effects of melatonin were found in both paediatric cohorts with more marked effects in the children with DS. Melatonin mediates immune response through a wide array of mechanisms and this immunomodulator may buffer the inflammatory response by regulating pro and anti-inflammatory signalling.

Impact: We highlight that melatonin mediates its immune response through a wide array of mechanisms, its effects appear to be dose dependant and children with Down syndrome may be more receptive to treatment with it. Immunomodulatory effects of melatonin were demonstrated with marked effects in the children with Down syndrome with a reduction of MyD88, IL-1ß and NLRP3 expression in whole-blood samples. Melatonin is a proposed anti-inflammatory agent with a well-established safety profile, that has the potential for mitigation of pro- and anti-inflammatory cytokines in paediatric Down syndrome cohorts, though further clinical trials are warranted.

Citing Articles

Melatonin: a positive influencer of inflammation in neonatal encephalopathy.

Pang R, Molloy E, Robertson N Pediatr Res. 2025; .

PMID: 39833346 DOI: 10.1038/s41390-025-03876-7.

Melatonin, an Antitumor Necrosis Factor Therapy.

Alvarez-Lopez A, Cruz-Chamorro I, Lardone P, Bejarano I, Aspiazu-Hinostroza K, Ponce-Espana E J Pineal Res. 2024; 77(1):e70025.

PMID: 39740227 PMC: 11685806. DOI: 10.1111/jpi.70025.

Periodontal disease in down syndrome: Predisposing factors and potential non-surgical therapeutic approaches.

Ghaffarpour M, Karami-Zarandi M, Rahdar H, Feyisa S, Taki E J Clin Lab Anal. 2024; 38(1-2):e25002.

PMID: 38254289 PMC: 10829694. DOI: 10.1002/jcla.25002.

Innovating Therapies for Down Syndrome: An International Virtual Conference of the T21 Research Society.

Hamlett E, Flores-Aguilar L, Handen B, Potier M, Granholm A, Sherman S Mol Syndromol. 2023; 14(2):89-100.

PMID: 37064334 PMC: 10090974. DOI: 10.1159/000526021.

References

Martinez E, Castaneda D, Jaramillo S, Iregui A, Quinonez T, Rodriguez J . Altered immune parameters correlate with infection-related hospitalizations in children with Down syndrome. Hum Immunol. 2016; 77(7):594-9. DOI: 10.1016/j.humimm.2016.05.004. View

Ram G, Chinen J . Infections and immunodeficiency in Down syndrome. Clin Exp Immunol. 2011; 164(1):9-16. PMC: 3074212. DOI: 10.1111/j.1365-2249.2011.04335.x. View

Kusters M, Manders N, de Jong B, van Hout R, Rijkers G, de Vries E . Functionality of the pneumococcal antibody response in Down syndrome subjects. Vaccine. 2013; 31(52):6261-5. DOI: 10.1016/j.vaccine.2013.09.070. View

Kusters M, Jol-van der Zijde E, Gijsbers R, de Vries E . Decreased response after conjugated meningococcal serogroup C vaccination in children with Down syndrome. Pediatr Infect Dis J. 2011; 30(9):818-9. DOI: 10.1097/INF.0b013e31822233f9. View

Kusters M, Jol-van der Zijde C, van Tol M, Bolz W, Bok L, Visser M . Impaired avidity maturation after tetanus toxoid booster in children with Down syndrome. Pediatr Infect Dis J. 2010; 30(4):357-9. DOI: 10.1097/INF.0b013e3181ff85a8. View

Zhang Y, Che M, Yuan J, Yu Y, Cao C, Qin X . Aberrations in circulating inflammatory cytokine levels in patients with Down syndrome: a meta-analysis. Oncotarget. 2017; 8(48):84489-84496. PMC: 5663613. DOI: 10.18632/oncotarget.21060. View

Cetiner S, Demirhan O, Inal T, Tastemir D, Sertdemir Y . Analysis of peripheral blood T-cell subsets, natural killer cells and serum levels of cytokines in children with Down syndrome. Int J Immunogenet. 2010; 37(4):233-7. DOI: 10.1111/j.1744-313X.2010.00914.x. View

Izumi Y, Sugiyama S, Shinozuka O, Yamazaki T, Ohyama T, Ishikawa I . Defective neutrophil chemotaxis in Down's syndrome patients and its relationship to periodontal destruction. J Periodontol. 1989; 60(5):238-42. DOI: 10.1902/jop.1989.60.5.238. View

Araya P, Waugh K, Sullivan K, Nunez N, Roselli E, Smith K . Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity. Proc Natl Acad Sci U S A. 2019; 116(48):24231-24241. PMC: 6883781. DOI: 10.1073/pnas.1908129116. View

10.

Hilton J, Fitzgerald D, Cooper D . Respiratory morbidity of hospitalized children with Trisomy 21. J Paediatr Child Health. 1999; 35(4):383-6. DOI: 10.1046/j.1440-1754.1999.00386.x. View

11.

Fitzgerald P, Leonard H, Pikora T, Bourke J, Hammond G . Hospital admissions in children with down syndrome: experience of a population-based cohort followed from birth. PLoS One. 2013; 8(8):e70401. PMC: 3742744. DOI: 10.1371/journal.pone.0070401. View

12.

Garrison M, Jeffries H, Christakis D . Risk of death for children with down syndrome and sepsis. J Pediatr. 2005; 147(6):748-52. DOI: 10.1016/j.jpeds.2005.06.032. View

13.

Broers C, Gemke R, Weijerman M, van der Sluijs K, Marceline van Furth A . Increased pro-inflammatory cytokine production in Down Syndrome children upon stimulation with live influenza A virus. J Clin Immunol. 2011; 32(2):323-9. DOI: 10.1007/s10875-011-9625-4. View

14.

Du Y, Shan L, Cao Z, Feng J, Cheng Y . Prevalence of celiac disease in patients with Down syndrome: a meta-analysis. Oncotarget. 2018; 9(4):5387-5396. PMC: 5797057. DOI: 10.18632/oncotarget.23624. View

15.

Ramos da Rosa Utiyama S, Nisihara R, Nass F, Oliveira N, Fiedler P, Messias-Reason I . Autoantibodies in patients with Down syndrome: early senescence of the immune system or precocious markers for immunological diseases?. J Paediatr Child Health. 2007; 44(4):182-6. DOI: 10.1111/j.1440-1754.2007.01229.x. View

16.

Ferreira R, Michel R, Greghi S, Resende M, Santana A, Damante C . Prevention and Periodontal Treatment in Down Syndrome Patients: A Systematic Review. PLoS One. 2016; 11(6):e0158339. PMC: 4927059. DOI: 10.1371/journal.pone.0158339. View

17.

Reiter R, Poeggeler B, Heiden S, CLAYTON R . Twenty-four hour urinary excretion of 6-hydroxymelatonin sulfate in Down syndrome subjects. J Pineal Res. 1996; 20(1):45-50. DOI: 10.1111/j.1600-079x.1996.tb00238.x. View

18.

Acuna-Castroviejo D, Escames G, Venegas C, Diaz-Casado M, Lima-Cabello E, Lopez L . Extrapineal melatonin: sources, regulation, and potential functions. Cell Mol Life Sci. 2014; 71(16):2997-3025. PMC: 11113552. DOI: 10.1007/s00018-014-1579-2. View

19.

Bourne R, Mills G . Melatonin: possible implications for the postoperative and critically ill patient. Intensive Care Med. 2006; 32(3):371-9. DOI: 10.1007/s00134-005-0061-x. View

20.

Sanchez-Barcelo E, Mediavilla M, Reiter R . Clinical uses of melatonin in pediatrics. Int J Pediatr. 2011; 2011:892624. PMC: 3133850. DOI: 10.1155/2011/892624. View