The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10

Abstract

The bacterial metabolite 4-methylphenol (<i>para</i>-cresol or <i>p</i>-cresol) and its derivative <i>p</i>-cresyl sulfate (<i>p</i>CS) are elevated in the urine and feces of children with autism spectrum disorder (ASD). It has been shown that <i>p</i>-cresol administration induces social behavior deficits and repetitive behavior in mice. However, the mechanisms of <i>p</i>-cresol, specifically its metabolite <i>p</i>CS that can reach the brain, in ASD remain to be investigated. The <i>p</i>CS has been shown to inhibit LPS-stimulated inflammatory response. A Disintegrin And Metalloprotease 10 (ADAM10) and A Disintegrin And Metalloprotease 17 (ADAM17) are thought to regulate microglial immune response by cleaving membrane-bound proteins. In the present study, a neuroinflammation model of LPS-activated BV2 microglia has been used to unveil the potential molecular mechanism of <i>p</i>CS in ASD pathogenesis. In microglial cells <i>p</i>CS treatment decreases the expression or maturation of ADAM10 and ADAM17. In addition, <i>p</i>CS treatment attenuates TNF-α and IL-6 releases as well as phagocytosis activity of microglia. In in vitro ADAM10/17 inhibition experiments, either ADAM10 or ADAM17 inhibition reduces constitutive and LPS-activated release of TNF-α, TNFR-1 and IL-6R by microglial cells, while it increases constitutive and LPS-activated microglial phagocytotic activity. The in vivo results further confirm the involvement of ADAM10 and ADAM17 in ASD pathogenesis. In in utero VPA-exposed male mice, elevated concentration in serum of <i>p</i>-cresol-associated metabolites <i>p</i>CS and <i>p</i>-cresyl glucuronide (<i>p</i>CG) is associated with a VPA-induced increased ADAM10 maturation, and a decreased ADAM17 maturation that is related with attenuated levels of soluble TNF-α and TGF-β1 in the mice brain. Overall, the present study demonstrates a partial role of ADAM10 and ADAM17 in the derailed innate immune response of microglial cells associated with <i>p</i>CS-induced ASD pathogenesis.