Effects of a gut-selective integrin-targeted therapy in male mice exposed to early immune activation, a model for the study of autism spectrum disorder

Abstract

To clarify the role of gut mucosal immunity in ASD, we evaluated, in the early-life immune activation (EIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (α4β7 mAb), blocking the leukocyte homing into the gut mucosa. EIA is a double-hit variant of the maternal immune-activation (MIA) model, including both prenatal (Poly I:C) and postnatal (LPS) immune challenges. In C57BL6/J EIA male adult offspring mice, IL-1β and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4⁺α4β7⁺, unstimulated and stimulated IL-17A⁺ and stimulated IFN-γ⁺ lymphocytes in MLN and CD4⁺α4β7⁺ unstimulated and stimulated IL-17A⁺ and stimulated IFN-γ⁺ lymphocytes in the spleen. Treatment with anti-α4β7 mAb in EIA male mice was associated with colonic tissue IL-1β, and IL-17A mRNA content and percentage of CD4⁺ IL-17A⁺ and IFN-γ⁺ lymphocytes in MLN and spleens comparable to control mice. The anti-α4β7 mAb treatment rescue social novelty deficit showed in the three-chamber test by EIA male mice. Increased levels of IL-6 and IL-1β and decreased CD68 and TGF-β mRNAs were also observed in hippocampus and prefrontal cortex of EIA male mice together with a reduction of BDNF mRNA levels in all brain regions examined. Anti-α4β7 mAb treatment restored the expression of BDNF, TGF-β and CD68 in hippocampus and prefrontal cortex. Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first preclinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (α4β7+) lymphocytes expressing IL-17A.

Keywords: ASD mouse models; Autism spectrum disorder; Behavioral profile; Gut mucosal immunity; Gut-brain axis; Monoclonal antibody anti-α4β7; Neuroinflammation.