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Abstract:
Objective Intestinal epithelial cells (IECs) at the
internal/external interface orchestrate the mucosal
immune response. Paneth cells secrete antimicrobial
peptides and inflammatory mediators, protect from
pathogens and shape the commensal microbiota.
Prompted by the genetic association of the locus
harbouring the type I interferon (IFN) receptor (IFNAR1)
with Crohn’s disease, and a transcriptional signature for
type I IFN signalling in Paneth cells, we studied the
function of IFNAR1 in IECs.
Design Type I IFN signalling was studied in mice with
conditional deletion of Ifnar1 in IECs. Phenotype was
characterised at baseline, and gut microbiota
composition was assessed by 16S rDNA ribotyping. The
role of IFNAR1 was also investigated in experimental
colitis induced by dextran sodium sulfate (DSS) and
colitis-associated cancer induced by DSS in conjunction
with azoxymethane (AOM).
Results Ifnar1−/−(IEC) mice displayed expansion of Paneth
cell numbers and epithelial hyperproliferation compared
with Ifnar1-sufficient littermates. While Ifnar1−/−(IEC) mice
did not exhibit spontaneous inflammation or increased
severity in DSS colitis compared with Ifnar1+/+(IEC) mice,
they exhibited an increased tumour burden in the AOM/
DSS model. Both hyperproliferation and tumour promotion
were dependent on the microbial flora, as the differences
between genotypes were marked upon separately housing
mice, but disappeared when Ifnar1−/−(IEC) and Ifnar1+/+(IEC)
mice were co-housed. Accordingly, ribotyping revealed
marked differences between Ifnar1−/−(IEC) and Ifnar1+/+(IEC)
mice that where diminished upon co-housing.
Conclusions IFNAR1 in IECs, and Paneth cells in
particular, contributes to the regulation of the host–
microbiota relationship, with consequences for intestinal
regeneration and colitis-associated tumour formation.
