Cyclic AMP Pathway Suppress Autoimmune Neuroinflammation by Inhibiting Functions of Encephalitogenic CD4 T Cells and Enhancing M2 Macrophage Polarization at the Site of Inflammation

Abstract

Although it has been demonstrated that the cAMP pathway affects both adaptive and innate immune cell functions, its role in regulating T-cell‑mediated CNS autoimmune inflammation—such as experimental autoimmune encephalomyelitis (EAE)—was unclear. This study shows that activating adenylyl cyclase with Forskolin not only inhibits encephalitogenic CD4⁺ T cells but also upregulates microRNA‑124 in the CNS, which is associated with M2‑like polarization of microglia/macrophages. The data indicate that Forskolin administration after EAE onset significantly increases expression of M2 markers (Arg1, Mrc1, Fizz1, Ym1), reduces M1 markers (NOS2, CD86), and decreases CD4⁺ T cell infiltration in the CNS—leading to disease amelioration. Forskolin weakly affects CD4⁺ T cells peripherally or in vitro, supporting the hypothesis that the major effect is indirect: Forskolin promotes M2 polarization via the ERK pathway in macrophages, which in turn suppresses pathogenic T cell functions in the CNS.