Abstract
Systemic administration of polyinosinic:polycytidylic acid (poly I:C), mimics virally-induced activation of TLR3 signalling causing acute small intestine damage, but whether and how mucosal administration of poly I:C causes enteropathy is less clear. Our aim was to investigate the inflammatory pathways elicited after intraluminal administration of poly I:C and determine acute and delayed consequences of this locally induced immune activation. Intraluminal poly I:C induced rapid mucosal immune activation in C57BL/6 mice involving IFNβ and the CXCL10/CXCR3 axis, that may drive inflammation towards a Th1 profile. Intraluminal poly I:C also caused enteropathy and gut dysfunction in gliadin-sensitive NOD-DQ8 mice, and this was prolonged by concomitant oral administration of gliadin. Our results indicate that small intestine pathology can be induced in mice by intraluminal administration of poly I:C and that this is exacerbated by subsequent oral delivery of a relevant dietary antigen.
Highlights
Detection of components of microorganisms by a complex system of pattern recognition receptors leads to immune host defense
Analysis of expression of proinflammatory cytokines such as IL-18, IL-1b, IL-15 and IFNc,chemokines such as MCP1 and CXCL2, and anti- and proapoptotic molecules Bcl-2 and Bax, respectively, did not show any differences between groups.Since recognition of polycytidylic acid (poly I):C is mediated by TLR3, melanoma differentiation-associated gene 5 (MDA5) and RIGI and their expressions are modulated by poly I:C, we evaluated whether the expression of these receptors were induced in the small intestine of treated mice
We showed that induction of local small intestinal inflammation can be elicited by intraluminal administration of poly I:C to both wild type and gliadin-sensitive NOD-DQ8 mice
Summary
Detection of components of microorganisms by a complex system of pattern recognition receptors leads to immune host defense. Uncontrolled activation of these pathways may lead to pathology, as demonstrated in studies using intraperitoneal (ip) administration of double stranded RNA (dsRNA) that induces overactivation of TLR3 signalling [2,3,4,5]. In addition to TLR3, dsRNA sensors include two cytoplasmic receptors, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) [7]. McAllister C. et al. showed that signaling pathways activated through dsRNA sensors and TLR3/TRIF/caspase 8, drive intestinal pathology and host protection during viral infection. The role of locally induced, rather than systemic pathways in these models, remain unclear. More importantly there is a scarcity of models directly relevant to small intestinal induction of pathology and gut dysfunction
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