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Vitamin D3 action over intestinal mucosal during clinical evolution of Experimental Autoimmune Encephalomyelitis

Grant number: 19/13552-8
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2019
Effective date (End): July 31, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Alessandro dos Santos Farias
Grantee:Natália Brunetti Silva
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Multiple Sclerosis (MS) is a chronic autoimmune and demyelinating disease that affects the Central Nervous System (CNS) of young adults. As described in the literature, it is believed that MS is the result of a combination of environmental factors and genetic predisposition of the patient. Recent studies have evidenced the participation of vitamin D3 in the process of evolution of the disease and the experimental model of Experimental Autoimmune Encephalomyelitis (EAE). The low production and/or intake of this vitamin is among the environmental factors that may be related to predisposition to the disease. Since 1991, the immunomodulatory action of vitamin D3 and its active form on the clinical course of EAE has been known. Recently, our group demonstrated that dendritic cells are the main target for regulation of vitamin D3. In this study we demonstrate that vitamin D3 induces a tolerogenic profile in DCs dependent on the expression of the enzyme IDO, responsible of the tryptophan metabolism. Consequently, these cells stimulate the CD4+ Foxp3 + T lymphocytes with regulatory action. The recruitment and/or stimulation of regulatory CD4 + T lymphocytes decreases the inflammatory response in EAE and other autoimmune diseases. Interestingly, in our hand, the effect of oral vitamin D3 treatment was much higher than the effect of intraperitoneal treatment, in part this result contradicts some studies in the literature. However, in our study, we used the inactive form (cholecalciferol) of vitamin D3, and most of the successful studies in the intraperitoneal treatment used the active form (calcitriol) of vitamin D3. Thus, it is plausible to admit that the inactive form of vitamin D3 depends on properties of the intestinal mucosa for its immunomodulatory activity. In the last decade, several studies have shown that the integrity and activity of mucosal immunity is closely linked to the "quality" of the intestinal microbiota. The commensal microbiota is directly related to the maturation and activity of the immune response. Also, the host's immune system is directly related in maintaining symbiosis with the microbiota. Intestinal microbiota products, mainly Short Chain Fatty Acids (SCFA), have important immunoregulatory action and may be directly linked to the control or exacerbation of autoimmune diseases.In addition, the consumption of tryptophan by IDO generates kynurenine, a natural binder of the aryl hydrocarbon receptor (AhR). This receptor has complex effects on the immune system. In case of kynurenine metabolites, the effect caused by the receptor appears to be immunosuppressive. The AhR acts in suppression of the tumor immune response, in differentiation of Foxp3 + regulatory T cells and in decrease the immunogenicity of dendritic cells. Thus, it is possible that IDO metabolism products have an important role on T lymphocytes, both in the conversion and maintenance of Treg, and in an autocrine way in the maintenance of tolerogenic DCs. Noteworthy, SCFA, especially butyrate, has been recently shown to be an AhR linker. In parallel, butyrate can regulate the expression of IDO in intestinal epithelial cells. Thus, it is possible that the oral treatment with vitamin D3 regulates, directly or indirectly (via modification of the microbiota), the IDO/AhR axis in the intestinal mucosa. Modulation of this axis would explain the immunomodulatory effect of vitamin D3 on EAE, both for the induction of regulatory dendritic cells and in the activation or expansion of Treg cells. In view of the above facts, our aim in this project is to evaluate the action of oral vitamin D3 treatment on the immunity of the intestinal mucosa, as well as the direct or indirect participation of the intestinal microbiota in the immunomodulatory effect of vitamin D3. (AU)