ZAP-70 genotype disrupts the relationship between microbiota and host, leading to spondyloarthritis and ileitis in SKG mice
| Autor: | Rehaume LM, Mondot S, Aguirre de Cárcer D, Velasco J, Benham H, Hasnain SZ, Bowman J, Ruutu M, Hansbro PM, McGuckin MA, Morrison M, Thomas R |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Mice
Knockout Mice Inbred BALB C ZAP-70 Protein-Tyrosine Kinase Genotype Microbiota Ileitis Severity of Illness Index Interleukin-23 Arthritis & Rheumatology Toll-Like Receptor 4 Mice 1103 Clinical Sciences 1107 Immunology 1117 Public Health and Health Services Spondylarthritis Animals Genetic Predisposition to Disease |
| Popis: | ObjectiveThe spondyloarthritides share genetic susceptibility, interleukin-23 (IL-23) dependence, and the involvement of microbiota. The aim of the current study was to elucidate how host genetics influence gut microbiota and the relationship between microbiota and organ inflammation in spondyloarthritides.MethodsBALB/c ZAP-70(W163C) -mutant (SKG) mice, Toll-like receptor 4 (TLR-4)-deficient SKG mice, and wild-type BALB/c mice were housed under specific pathogen-free conditions. SKG and wild-type BALB/c mice were maintained under germ-free conditions, and some of these mice were recolonized with altered Schaedler flora. All of the mice were injected intraperitoneally with microbial β-1,3-glucan (curdlan). Arthritis, spondylitis, and ileitis were assessed histologically. Microbiome composition was analyzed in serial fecal samples obtained from mice that were co-housed beginning at the time of weaning, using 454 pyrosequencing. Infiltrating cells and cytokines in the peritoneal cavity were measured by flow cytometry and enzyme-linked immunosorbent assay. Cytokine, endoplasmic reticulum (ER) stress marker, and tight junction protein transcription was measured by quantitative real-time polymerase chain reaction.ResultsMicrobiota content and response to curdlan varied according to whether T cell receptor signal strength was normal or was impaired due to the ZAP-70(W163C) mutation. Curdlan triggered acute inflammation regardless of the presence of the SKG allele or microbiota. However, no or limited microbiota content attenuated the severity of arthritis. In contrast, ileal IL-23 expression, ER stress, lymph node IL-17A production, goblet cell loss, and ileitis development were microbiota-dependent. Ileitis but not arthritis was suppressed by microbiota transfer upon co-housing SKG mice with wild-type BALB/c mice, as well as by TLR-4 deficiency.ConclusionThe interaction between immunogenetic background and host microbiota leads to an IL-23-dependent loss of mucosal function, triggering ileitis in response to curdlan. |
| Databáze: | OpenAIRE |
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