ICMI 2015

OR.71 Spontaneous Innate Immune Mediated Colitis

Friday, July 17, 2015: 11:15 AM
Salon 7, Ground Floor (Maritim Hotel)
Diana La Torre , University of Notre Dame, south bend, IN, United States
Stephen Murphy, PhD , University of Chicago, Chicago, IL
Lesley Rhee, MD , University of Chicago, Chicago, IL
David Boone, PhD , Indiana University School of Medicine, South Bend, IN
TNFAIP3 is an anti-inflammatory enzyme inhibiting NF-κB through a negative feedback loop. In intestinal epithelial cells (IEC), TNFAIP3 prevents IEC apoptosis and increases barrier function. To assess the role of IEC expression of TNFAIP3 on intestinal innate immune function, we crossed RAG-1-/- mice and villin-TNFAIP3 (v-TNFAIP3) transgenic mice, which constitutively TNFAIP3 in IEC. Neither RAG-1-/- nor v-TNFAIP3 mice spontaneously develop colitis, however, all v-TNFAIP3 x RAG-1-/- mice exhibited early onset spontaneous colitis by 4 weeks of age. This colitis was prevented by antibiotic treatment, implicating microbes in the pathology of this model. Gene arrays and immunohistochemistry revealed that v-TNFAIP3 x RAG-1-/- mice had altered anti-microbial peptide (AMP) expression in the colon, including decreased Ang4 and increased Reg3b expression.  RAG-1-/- mice maintained the largely sterile inner-mucus layer of the gut but the inner mucus was infiltrated by microbes in v-TNFAIP3 x RAG-1-/- mice. Cytokine immunoarrays of colonic tissue from v-TNFAIP3 x RAG-1-/- mice showed an elevation of IL-1α, but not other cytokines typically elevated in other models of colitis. Thus, our model is that expression of TNFAIP3 in IEC leads to inhibition of NF-kB dependent AMP production, resulting in invasion of the inner mucus layer by a subset of microbes that drive IL-1a production leading to innate-immune mediated colitis.  These findings may be particularly relevant to understanding the pathology of inflammatory bowel disease in immunocompromised individuals.