AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

Abstract

The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood–brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10lowIL-23/IL-1β/IL-6high), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35–55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35–55–primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4+ T cells were due to an autocrine effect of IL-1β/IL-23–mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype–Th17 axis in an animal model of multiple sclerosis.

ANG II facilitated CD11+Ly6Chi cells reprogramming into M1-like macrophage through Erk1/2 or p38-Stat3 pathway and involved in EAM

“…Macrophage functions are settled in response to microenvironmental signals, which drive the macrophage acquisition of polarized programs, M1 and M2 dichotomy. M1 macrophage has proinflammatory and cytotoxic capacities as well as stronger capacity to induce Ag‐specific (MyHC‐α 614–629 ) T‐cell response . Conversely, M2 macrophage expresses higher levels of Arg‐1, neurotrophic factors, and has been implicated in resolution of inflammation and remodeling of injury tissue or organ as well as promotion of Th2 response .…”

The evolving role of neuro‐immune interaction in brain repair after cerebral ischemic stroke

“…Demyelination was exacerbated in EAE animals when microglia M2 polarization was inhibited . However, the M1 type macrophage, together with the Th17 cells are involved in the demyelination in the animal model of sclerosis . The evidence of macrophage's impact on white matter intergrity is also conflicting.…”

Role of diet, gut microbiota, and metabolism in multiple sclerosis and neuromyelitis optica

“…As clearly shown by the pharmacological effect of DMF, suppressing molecules related to glycolysis, and glutaminolysis will lead to inhibition of effector T cells. 35 On the contrary, enhancement of fatty acid oxidation will promote Treg development, and support the resolution of autoimmunity. 30 Additional observation is also obtained by the studies focusing on adenosine monophosphate-activated kinase, the critical metabolic regulator facilitating the M2 phenotype.…”

“…Adenosine monophosphate-activated kinase activators attenuate the progression of EAE, and adenosine monophosphate-activated kinase-deficient mice show a more severe disease course of EAE. 35 On the contrary, enhancement of fatty acid oxidation will promote Treg development, and support the resolution of autoimmunity. In addition, inhibition of fatty acid synthesis could impair Th17 differentiation, and promote Treg development.…”