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Assessment of Lymphocyte Migration in an Ex Vivo Transmigration System
Published on: September 20, 2019
Children with atopic histories exhibit impaired lipopolysaccharide-induced Toll-like receptor-4 signalling in
D Préfontaine1, A-A Banville-Langelier, P-O Fiset
1Meakins Christie Laboratories and Montreal Children's Hospital Research Institute, McGill University Health Center Research Institute, Montreal, QC, Canada.
Insights
Children with a history of atopic disease show impaired immune cell responses to lipopolysaccharide (LPS). This defective Toll-like receptor 4 (TLR-4) signaling in monocytes suggests a link between atopy and reduced innate immune function.
Area of Science:
- Immunology
- Allergy Research
- Innate Immunity
Background:
- The hygiene hypothesis suggests early microbial exposure protects against allergies.
- The impact of atopic disease on immune cell lipopolysaccharide (LPS) response is not well understood.
- Previous work indicated high Toll-like receptor (TLR)-4 expression on children's nasal CD4(+) cells.
Purpose of the Study:
- To investigate if children with allergic disease exhibit impaired LPS responses in circulating CD4(+) leucocytes.
- To compare LPS-induced signaling pathways in immune cells from atopic and non-atopic children.
Main Methods:
- Peripheral blood mononuclear cells from children and adults with/without atopy were cultured with IL-4 or LPS.
- Flow cytometry assessed surface markers (TLR-4, CD14, CD4, CD3) and intracellular signaling (phosphorylated ERK, p38 MAPK).
Main Results:
- Atopic children showed impaired LPS-induced phosphorylation of ERK and p38 MAPK in CD4(+) monocytes.
- Recombinant IL-4 mimicked the decreased LPS signaling observed in atopic subjects.
- TLR-4 expression on monocytes decreased with age in atopic children but not non-atopic children.
- CD4(+) T lymphocytes demonstrated limited LPS responsiveness irrespective of atopic status.
Conclusions:
- Children with atopic histories exhibit defective LPS recognition on circulating CD4(+) leucocytes.
- CD4(+) TLR4(+) monocytes from atopic children failed to phosphorylate MAPKs, indicating impaired TLR-4-mediated innate immunity.
- Atopic disease history is associated with compromised innate immune responses compared to non-atopic children.
Background:
The hygiene hypothesis states that early exposure to bacterial products such as lipopolysaccharide (LPS) may be protective against the development of allergic diseases. Whether atopic disease affects the ability of immune cells to respond to LPS is unclear. Our laboratory has demonstrated previously that children express high levels of Toll-like receptor (TLR)-4 on CD4(+) cells in nasal mucosa.
Objective:
To determine if children with a history of allergic disease have impaired responses to LPS on circulating CD4(+) leucocytes.
Methods:
Peripheral blood mononuclear cells from children (aged 2-18) and adults with or without a history of atopic conditions were cultured with/without IL-4 or LPS for up to 24 h. Expression of surface TLR-4, CD14, CD4, CD3, as well as of intracellular phosphorylated (p42/p44) ERK and p38 mitogen-activated protein kinase (MAPK) were assessed by flow cytometry.
Results:
A history of atopy in children was associated with impaired LPS-induced TLR-4-dependent phosphorylation of (p42/44) ERK and p38 MAPK by CD4(+) monocytes. Decreased LPS signalling was reproduced by pre-incubation of control cells with recombinant IL-4. LPS stimulation also decreased TLR-4 expression on monocytes from children without atopic histories but not from atopic subjects. CD4(+) T lymphocytes showed limited LPS responsiveness, regardless of atopic status. In contrast with non-atopic children, TLR-4 expression on monocytes of children with atopic histories decreased as a function of age.
Conclusions:
This study provides evidence for defective LPS recognition on circulating CD4(+) leucocytes of subjects with atopic histories compared with those from non-atopic children. CD4(+) TLR4(+) monocytes from children with atopic histories failed to phosphorylate MAPKs. Our results suggest that a history of atopic disease is associated with impaired TLR-4-mediated innate immune function compared with non-atopic children.
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