Ingested ACTH blocks Th17 production by inhibiting GALT IL-6

Area of Science:

• Immunology and Neuroscience
• Autoimmune disease modeling
• Therapeutic mechanisms of action

Background:

• Experimental autoimmune encephalomyelitis (EAE) is a CNS inflammatory disease model mirroring multiple sclerosis (MS).
• Oral adrenocorticotropic hormone (ACTH) has shown potential in reducing EAE clinical signs, decreasing pro-inflammatory cytokines like IL-17 and IFN-γ, and increasing regulatory T cells (Tregs).
• The precise mechanism by which oral ACTH exerts these immunomodulatory effects remains unclear.

Purpose of the Study:

• To investigate the role of interleukin-6 (IL-6) in the gut-associated lymphoid tissue (GALT) as a mediator of oral ACTH's effects in EAE.
• To determine if oral ACTH administration inhibits IL-6 production within the GALT during EAE.

Main Methods:

• Mice with EAE were induced using MOG peptide 35-55.
• During active EAE, mice were orally administered either ACTH 1-39 or a scrambled control peptide (scrambled α-MSH).
• Immune cells from the lamina propria, spleen, and CNS were analyzed for cytokine production (IL-6, IL-17, IFN-γ) and T cell populations (Tregs).

Main Results:

• Oral ACTH administration significantly inhibited ongoing EAE clinical disease.
• In the gut lamina propria, ACTH-treated mice showed reduced IL-6 and IL-17 producing lymphocytes compared to controls.
• ACTH treatment led to decreased IL-17 and IFN-γ producing spleen cells, an increase in CD4+ FoxP3+ Tregs in the spleen, and reduced IFN-γ producing CNS lymphocytes.

Conclusions:

• Ingested ACTH effectively suppresses clinical symptoms of EAE.
• The therapeutic benefit of oral ACTH in EAE is mediated by the inhibition of IL-6 production within the gut-associated lymphoid tissue (GALT).
• This study elucidates a key mechanism for oral ACTH's immunomodulatory action in autoimmune CNS disease.