Landon J Dittel1, Bonnie N Dittel2, Staley A Brod3. 1. Department of Neurology, Medical College of Wisconsin, United States of America. 2. Versiti Blood Research Institute and the Department of Microbiology and Immunology, Medical College of Wisconsin, United States of America. 3. Department of Neurology, Medical College of Wisconsin, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226, United States of America. Electronic address: sbrod@mcw.edu.
Abstract
BACKGROUND: EAE is an inflammatory autoimmune process of the CNS that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. Oral ACTH (adrenocorticotropic hormone) can decrease clinical disease, IL-17 and Th1-like encephalitogenic IFN-γ secretion and increase Treg frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases Treg cell frequencies is unknown. OBJECTIVE: IL-6 is a pivotal cytokine in the gut that determines the relative frequencies of Th17 vs Treg cells. We examined whether oral ACTH inhibited IL-6 in the gut associated lymphoid tissue (GALT) in EAE. DESIGN/ METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with scrambled ACTH (scrambled melanocyte stimulating hormone [scrambled α-MSH]) or ACTH 1-39 during ongoing disease. RESULTS: Ingested (oral) ACTH inhibited ongoing clinical disease. In the lamina propria (LP) immune compartment, there were significantly less CD11b + IL-6 and IL-17 producing lymphocytes from ACTH fed mice compared to s-MSH fed mice. There was also a decrease in the frequency of IL-17 and IFN-γ producing spleen cells and an increase in CD4 + FoxP3+ Treg cell frequency in ACTH fed mice compared to s-MSH fed control spleens. There were less IFN-γ producing CNS lymphocytes in ACTH fed mice compared to s-MSH fed control CNS. CONCLUSIONS: Ingested ACTH inhibits EAE clinical disease by inhibiting IL-6 in the GALT.
BACKGROUND: EAE is an inflammatory autoimmune process of the CNS that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. Oral ACTH (adrenocorticotropic hormone) can decrease clinical disease, IL-17 and Th1-like encephalitogenic IFN-γ secretion and increase Treg frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases Treg cell frequencies is unknown. OBJECTIVE:IL-6 is a pivotal cytokine in the gut that determines the relative frequencies of Th17 vs Treg cells. We examined whether oral ACTH inhibited IL-6 in the gut associated lymphoid tissue (GALT) in EAE. DESIGN/ METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with scrambled ACTH (scrambled melanocyte stimulating hormone [scrambled α-MSH]) or ACTH 1-39 during ongoing disease. RESULTS: Ingested (oral) ACTH inhibited ongoing clinical disease. In the lamina propria (LP) immune compartment, there were significantly less CD11b + IL-6 and IL-17 producing lymphocytes from ACTH fed mice compared to s-MSH fed mice. There was also a decrease in the frequency of IL-17 and IFN-γ producing spleen cells and an increase in CD4 + FoxP3+ Treg cell frequency in ACTH fed mice compared to s-MSH fed control spleens. There were less IFN-γ producing CNS lymphocytes in ACTH fed mice compared to s-MSH fed control CNS. CONCLUSIONS: Ingested ACTH inhibits EAE clinical disease by inhibiting IL-6 in the GALT.
Authors: Elena Niculet; Valentin Chioncel; Alina M Elisei; Magdalena Miulescu; Olimpia D Buzia; Lawrence C Nwabudike; Mihaela Craescu; Miruna Draganescu; Florin Bujoreanu; Elisabeta Marinescu; Manuela Arbune; Diana Sabina Radaschin; Carmen Bobeica; Aurel Nechita; Alin L Tatu Journal: Exp Ther Med Date: 2021-01-25 Impact factor: 2.447
Authors: Jing Zhao; Liwei Jiang; Mayuko Uehara; Naima Banouni; Basmah S Al Dulaijan; Jamil Azzi; Takaharu Ichimura; Xiaofei Li; Petr Jarolim; Paolo Fiorina; Stefan G Tullius; Joren C Madsen; Vivek Kasinath; Reza Abdi Journal: JCI Insight Date: 2021-07-08