Date of Award
Spring 2023
Degree Name
Bachelor of Arts
Department
Biology; College of Arts & Sciences
First Advisor
Dr. Richard Kaplan
Abstract
Autoimmune Thyroiditis (AIT) is a prevalent autoimmune disease affecting approximately 2% of the population. Characterized by the gradual loss of thyroid function through an autoimmune attack on the thyroid gland, the disease manifests symptoms that negatively affect one’s quality of life. The mechanisms behind the disease’s pathophysiology are not fully understood; however, researchers are examining the involvement of the NLRP3 inflammasome in the disease. This thesis will address the question of whether Vitamin D can act as an inhibitor of the NLRP3 inflammasome and attenuate the progression of AIT in mouse model. Current investigations explore the effects of NLRP3 inhibition on the AIT mouse model, Experimental Autoimmune Thyroiditis (EAT), and analyze the effect of Vitamin D on the inflammasome. Research conducted by Ding involved groups of AIT and non-AIT humans as well as EAT mice, with one group injected with known NLRP3 inhibitor, MCC950. Rao studied the signaling mechanism and activation of the NLRP3 inflammasome by Vitamin D Receptor (VDR) in two human cell lines, HEK293T cells and THP1 cells, and bone marrow-derived macrophages (BMDMs) from two mouse strains, Nlrp3-/- and Vdr-/-. Major analyses of data from both studies were completed using qPCR, immunoblotting, and ELISAs for mRNA expression, cleaved caspase-1, caspase-1, and IL-1β levels, VDR expression, ASC oligomers, NLRP3 ubiquitination, and BRCC3 protein. These tests revealed increased NLRP3 expression and increased levels of cleaved caspase-1, caspase-1, and IL-1β in AIT/EAT thyroid samples. Results also presented that VDR suppressed NLRP3 activation via blocking BRCC3 binding and NLRP3 deubiquitination. VDR also inhibited caspase-1 activation and IL-1β secretion in VDR-restored Vdr-/- BMDMs, and this inhibition was further enhanced by Vitamin D treatment. These findings suggest that Vitamin D enhances the effects of VDR-mediated NLRP3 inhibition suppressing the progression of Autoimmune Thyroiditis.
Recommended Citation
Mandac, Alexzon, "Vitamin D Enhanced Vitamin D Receptor (VDR) Inhibition of NLRP3 Inflammasome Activation Can Attenuate the Development of Autoimmune Thyroiditis" (2023). Capstone Showcase. 5.
https://scholarworks.arcadia.edu/showcase/2023/bio/5
Included in
Endocrine System Diseases Commons, Immune System Diseases Commons, Immunopathology Commons, Medical Immunology Commons
Vitamin D Enhanced Vitamin D Receptor (VDR) Inhibition of NLRP3 Inflammasome Activation Can Attenuate the Development of Autoimmune Thyroiditis
Autoimmune Thyroiditis (AIT) is a prevalent autoimmune disease affecting approximately 2% of the population. Characterized by the gradual loss of thyroid function through an autoimmune attack on the thyroid gland, the disease manifests symptoms that negatively affect one’s quality of life. The mechanisms behind the disease’s pathophysiology are not fully understood; however, researchers are examining the involvement of the NLRP3 inflammasome in the disease. This thesis will address the question of whether Vitamin D can act as an inhibitor of the NLRP3 inflammasome and attenuate the progression of AIT in mouse model. Current investigations explore the effects of NLRP3 inhibition on the AIT mouse model, Experimental Autoimmune Thyroiditis (EAT), and analyze the effect of Vitamin D on the inflammasome. Research conducted by Ding involved groups of AIT and non-AIT humans as well as EAT mice, with one group injected with known NLRP3 inhibitor, MCC950. Rao studied the signaling mechanism and activation of the NLRP3 inflammasome by Vitamin D Receptor (VDR) in two human cell lines, HEK293T cells and THP1 cells, and bone marrow-derived macrophages (BMDMs) from two mouse strains, Nlrp3-/- and Vdr-/-. Major analyses of data from both studies were completed using qPCR, immunoblotting, and ELISAs for mRNA expression, cleaved caspase-1, caspase-1, and IL-1β levels, VDR expression, ASC oligomers, NLRP3 ubiquitination, and BRCC3 protein. These tests revealed increased NLRP3 expression and increased levels of cleaved caspase-1, caspase-1, and IL-1β in AIT/EAT thyroid samples. Results also presented that VDR suppressed NLRP3 activation via blocking BRCC3 binding and NLRP3 deubiquitination. VDR also inhibited caspase-1 activation and IL-1β secretion in VDR-restored Vdr-/- BMDMs, and this inhibition was further enhanced by Vitamin D treatment. These findings suggest that Vitamin D enhances the effects of VDR-mediated NLRP3 inhibition suppressing the progression of Autoimmune Thyroiditis.