Journal Article

Estrogen-induced compensatory mechanisms protect IL-10-deficient mice from developing EAE

Kent, Gail, Vandenbark, Arthur A., Seifert, Hilary A., Gerstner, Grant, Offner, Halina

2019

Overview

Background IL-10 knockout (KO) mice are protected from experimental autoimmune encephalomyelitis (EAE) with low-dose estrogen (E2) treatment similar to wild-type (WT) mice. Previous studies have demonstrated a decrease in tumor necrosis factor in all E2-treated groups, which led to the protection of the mice. Methods This study used IL-10 KO mice and WT mice treated either with E2 or sham pellets 7 days prior to induction of EAE. Mice were observed for 21 days post-immunization. The spleen, inguinal lymph nodes, and brain were evaluated by flow cytometry. Spinal cords were evaluated using a cytokine/chemokine array, RT-PCR, and histology. Results This study demonstrates that E2 treatment induced three heightened regulatory mechanisms that potentially protect IL-10 KO mice from EAE: (1) an increase in programmed death-ligands 1 and 2 on monocytes and macrophages in the periphery and within the CNS; (2) an increase in CD73 in the inflamed CNS, which can increase the production of the anti-inflammatory molecule adenosine; and (3) a decrease in CD4 + CD25 + FoxP3 + regulatory T cells in the spleen. Together, these factors comprise an alternative compensatory mechanism that significantly downregulates key pro-inflammatory cytokine, chemokine, and chemokine receptor genes which are enhanced in the spinal cord of IL-10 KO mice. This group of E2-treated mice remained asymptomatic after EAE challenge similar to E2-treated WT mice, despite their having more T and B lymphocytes in the brain, and modestly increased demyelination in the spinal cord. Conclusion These results indicate that previously unrecognized compensatory mechanisms of EAE protection are stimulated by E2 in the absence of IL-10, which can provide disease protection comparable to the IL-10-dependent effects induced by E2 in WT mice.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Animals / Autoimmune diseases / Biomedical and Life Sciences / Biomedicine / Development and progression / Drug Implants - administration & dosage / EAE inhibition / Encephalomyelitis / Encephalomyelitis, Autoimmune, Experimental - metabolism / Encephalomyelitis, Autoimmune, Experimental - prevention & control / Estrogen (E2) / Estrogens / Estrogens - administration & dosage / Female / Health aspects / IL-10 / Immunology / Interleukin-10 / Interleukin-10 - deficiency / Mice / Mice, Inbred C57BL / Mice, Knockout / Neurobiology / Neurology / Neurosciences / PD-1 ligands / Regulatory B and T cells / Tumor necrosis factor