Interleukin-4 and STAT6 promoter polymorphisms but not interleukin-10 or 13 are essential for schistosomiasis and associated disease burden among Nigerian children

Adedokun, Samuel Adeyinka; Seamans, Brooke N.; Cox, Natalya T.; Liou, Gialeigh; Akindele, Akeem Abiodun; Li, Yang; Ojurongbe, Olusola; Thomas, Bolaji N.

doi:10.1016/j.meegid.2018.07.012

Cited by 14 publications

(13 citation statements)

References 29 publications

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“…Research by Adedokun and his colleagues suggests that the IL-4 promoter region is a predisposing factor for schistosomiasis and is critical in regulating the disease burden and that carriers of the rs2243250 T/T mutation are more severely affected. With the deletion of STAT6, the rs3024974T/T variant among infected children indicated the need for the STAT6 promoter gene in provoking schistosomiasis susceptibility in Nigeria [63]. With the application of mutant mice, the role of STAT6 activation in the study of fibrosis mechanisms is demonstrated.…”

Section: Discussionmentioning

confidence: 99%

C/EBP Homologous Protein (CHOP) Activates Macrophages and Promotes Liver Fibrosis inSchistosoma japonicum-Infected Mice

Duan

Yang

Peng

et al. 2019

Journal of Immunology Research

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CCAAT/enhancer-binding homologous protein (CHOP), a transcriptional regulator induced by endoplasmic reticulum stress (ER stress) is a pivotal factor in the ER stress-mediated apoptosis pathway. Previous studies have shown that CHOP is involved in the formation of fibrosis in a variety of tissues and is associated with alternative macrophage activation. The role of CHOP in the pathologic effects of liver fibrosis in schistosomiasis has not been reported, and underlying mechanisms remain unclear. This study is aimed at understanding the effect of CHOP on liver fibrosis induced by Schistosoma japonicum (S. japonicum) in vivo and clarifying its mechanism. C57BL/6 mice were infected with cercariae of S. japonicum through the abdominal skin. The liver fibrosis was examined. The level of IL-13 was observed. The expressions of CHOP, Krüppel-like factor 4 (KLF4), signal transducer and activator of transcription 6 (STAT6), phosphorylation STAT6, interleukin-13 receptor alpha 1 (IL-13Rα1), and interleukin-4 receptor alpha (IL-4Rα) were analysed. The eosinophilic granuloma and collagen deposition were found around the eggs in mice infected for 6 and 10 weeks. IL-13 in plasma and IL-13Rα1 and IL-4Rα in liver tissue were significantly increased. The phosphorylated STAT6 was enhanced while Krüppel-like factor 4 (KLF4) was decreased in liver tissue. The expression of CHOP and colocalization of CHOP and CD206 were increased. Overall, these results suggest that CHOP plays a critical role in hepatic fibrosis induced by S. japonicum, likely through promoting alternative activation of macrophages.

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Section: Discussionmentioning

confidence: 99%

C/EBP Homologous Protein (CHOP) Activates Macrophages and Promotes Liver Fibrosis inSchistosoma japonicum-Infected Mice

Duan

Yang

Peng

et al. 2019

Journal of Immunology Research

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“…One important principle underpinning schistosomal pathogenesis, independent of parasite species, is the importance of IL-4. For instance, the onset, development, and progression of the granulomatous response and egg shedding during Schistosoma japonicum and S. haematobium infection, respectively, are regulated by the IL-4 signaling cascade (17,41). Signaling through the IL-4 receptor (IL-4R␣) also drives the chronic inflammatory response to the tissue-lodged eggs, which determines the gran- uloma size and its cellular and matrix composition (18,42) and regulates the fibrotic repair response and presumably subsequent carcinogenic sequelae.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis

Mbanefo

et al. 2020

Infect Immun

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Interleukin-4 (IL-4) is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis by injecting the bladder walls of IL-4 receptor-alpha knockout (Il4ra−/−) and wild-type mice with S. haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial proliferation, cell cycle, and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of granulomatous responses to bladder-wall-injected S. haematobium eggs in Il4ra−/− versus wild-type mice. S. haematobium egg injection triggered significant urothelial proliferation, including evidence of urothelial hyper-diploidy and cell cycle skewing in wild-type but not Il4ra−/− mice. Urothelial exposure to IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show that IL-4 signaling is required for key pathogenic features of urogenital schistosomiasis and that particular aspects of this signaling pathway may exert these effects directly on the urothelium. These findings point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis.

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“…The program SNPstats [44] was used to estimate allelic and genotypic frequencies, testing the Hardy-Weinberg equilibrium for the three loci under study: CD28 (rs3559399), CD209 (rs4804803) and STAT6 (rs3024974), with SNP's rejected on the threshold of p < 0.05, as described by [45]; association analysis was performed for each SNP separately. Allelic and genotypic frequencies between controls and malaria-infected individuals were as previously described.…”

Section: Discussionmentioning

confidence: 99%

CD209 and Not CD28 or STAT6 Polymorphism Mediates Clinical Malaria and Parasitemia among Children from Nigeria

et al. 2020

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Malaria remains a significant disease, causing epic health problems and challenges all over the world, especially in sub-Saharan Africa. CD209 and CD28 genes act as co-stimulators and regulators of the immune system, while the STAT6 gene has been reported to mediate cytokine-induced responses. Single nucleotide polymorphisms of these genes might lead to differential disease susceptibility among populations at risk for malaria, due to alterations in the immune response. We aim to identify key drivers of the immune response to malaria infection among the three SNPs: CD209 (rs4804803), CD28 (rs35593994) and STAT6 (rs3024974). After approval and informed consent, we genotyped blood samples from a total of 531 children recruited from Nigeria using the Taqman SNP genotyping assay and performed comparative analysis of clinical covariates among malaria-infected children. Our results reveal the CD209 (rs4804803) polymorphism as a susceptibility factor for malaria infection, significantly increasing the risk of disease among children, but not CD28 (rs35593994) or STAT6 (rs3024974) polymorphisms. Specifically, individuals with the homozygous mutant allele (rs4804803G/G) for the CD209 gene have a significantly greater susceptibility to malaria, and presented with higher mean parasitemia. This observation may be due to a defective antigen presentation and priming, leading to an ineffective downstream adaptive immune response needed to combat infection, as well as the resultant higher parasitemia and disease manifestation. We conclude that the CD209 gene is a critical driver of the immune response during malaria infection, and can serve as a predictor of disease susceptibility or a biomarker for disease diagnosis.

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Interleukin-4 and STAT6 promoter polymorphisms but not interleukin-10 or 13 are essential for schistosomiasis and associated disease burden among Nigerian children

Cited by 14 publications

References 29 publications

C/EBP Homologous Protein (CHOP) Activates Macrophages and Promotes Liver Fibrosis inSchistosoma japonicum-Infected Mice

C/EBP Homologous Protein (CHOP) Activates Macrophages and Promotes Liver Fibrosis inSchistosoma japonicum-Infected Mice

Interleukin-4 Signaling Plays a Major Role in Urogenital Schistosomiasis-Associated Bladder Pathogenesis

CD209 and Not CD28 or STAT6 Polymorphism Mediates Clinical Malaria and Parasitemia among Children from Nigeria

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