Microglial control of astrocytes in response to microbial metabolites

Abstract

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS). Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14 cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

“…Finally, higher kynurenine levels were associated with higher relapse rate. These results are generally in line with our understanding of the effects of different tryptophan metabolites on the risk and severity of MS 13, 14, 16. While metabolomics analyses have identified alterations in multiple metabolic processes in MS, these techniques have not been previously applied to pediatric MS and have not studied the tryptophan pathway as a whole 30.…”

“…Several of these metabolites are predominantly or exclusively produced by the gut microbiota and circulating levels are determined by the composition of the gut microbiota 35. Activation of AHR on astrocytes and microglia controls microglial activation, modulates the transcriptional program of astrocytes14 and dampens neuroinflammation. A Trp depleted diet worsened EAE which was reversed by Trp supplementation in a wild‐type mice, while mice lacking AHR on their astrocytes did not respond to Trp supplementation 13.…”

“…Several Trp metabolites downregulate CNS immune responses through activation of the aryl hydrocarbon receptor (AHR) on glial cells 13, 14. Interestingly, these Trp metabolites are produced by intestinal bacteria and this may affect the risk of MS 15.…”

Neuropathological features of “non‐motor” symptoms in multiple sclerosis and neuromyelitis optica

“…Furthermore, the progression of the disease and the transition to secondary progressive MS could result in a higher risk for cognitive impairments. 2): 6,13,24 (i) increased inflammation by meningeal ectopic lymphoid neogenesis; 30 (ii) oxidative activation of macrophages/microglia; [38][39][40] (iii) activation of astrocytes; 40,41 (iv) oligo-myelinic cytodegeneration with altered oligodendroglial heterogeneity; 42 (v) neuroaxonal cytodegeneration 28,41,43,44 and (vi) immune-mediated disruption of synaptic plasticity in the hippocampus. The Expanded Disability Status Scale is roughly linked to cognitive function, and screening tests for dementia (e.g.…”

“…13,19,24,25 Because core language abilities are often preserved, impaired cognitive functions are usually distinct from other neurodegenerative disorders, including Alzheimer's disease or frontotemporal dementia. 29,32 In particular, key elements promoting neuro-axonal cytodegeneration might induce axonal energy supply failures with abnormal accumulation of mitochondria, 28,[45][46][47][48] virtual and genuine hypoxia, 28,49 Wallerian degeneration, 44,50 age-related iron accumulation, 28 cross-talk with microglia or astrocytes, 40,41 and meningeal inflammation. the Mini-Mental State Scale) or self-report screening tests for cognition (e.g.…”