Transcriptomic and cellular decoding of functional brain connectivity changes reveal regional brain vulnerability to pro- and anti-inflammatory therapies

•Inflammation has heterogenous effects on brain function which are poorly understood.•INF-α and anti-TNF therapies produce differential decreases in regional connectivity.•The transcriptomic landscape of the brain explains regional variance in these effects.•INF-α is linked to constitutive expressio...

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Vydáno v:Brain, behavior, and immunity Ročník 102; s. 312 - 323
Hlavní autoři: Martins, D., Dipasquale, O., Davies, K., Cooper, E., Tibble, J., Veronese, M., Frigo, M., Williams, S.C.R., Turkheimer, F., Cercignani, M., Harrison, N.A.
Médium: Journal Article
Jazyk:angličtina
Vydáno: Netherlands Elsevier Inc 01.05.2022
Elsevier
Témata:
Anti-Inflammatory Agents - pharmacology
Anti-TNF
Brain
Depression
Global brain connectivity
Humans
Imaging transcriptomics
Immunology
Immunotherapy
Inflammation
Interferon-alpha - adverse effects
Interferon-α
Life Sciences
Neurobiology
Neurons and Cognition
Pharmaceutical sciences
Pharmacology
Transcriptome
Transcriptomic vulnerability
Tumor Necrosis Factor Inhibitors
Anti-TNF
Depression
Interferon-α
Transcriptomic vulnerability
Global brain connectivity
Imaging transcriptomics
ISSN:0889-1591, 1090-2139, 1090-2139
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Shrnutí:•Inflammation has heterogenous effects on brain function which are poorly understood.•INF-α and anti-TNF therapies produce differential decreases in regional connectivity.•The transcriptomic landscape of the brain explains regional variance in these effects.•INF-α is linked to constitutive expression of glial neuroinflammatory genes.•Anti-TNF therapies are linked to constitutive expression of glutamatergic genes. Systemic inflammation induces acute changes in mood, motivation and cognition that closely resemble those observed in depressed individuals. However, the mechanistic pathways linking peripheral inflammation to depression-like psychopathology via intermediate effects on brain function remain incompletely understood. We combined data from 30 patients initiating interferon-α treatment for Hepatitis-C and 20 anti-tumour necrosis factor (TNF) therapy for inflammatory arthritis and used resting-state functional magnetic resonance imaging to investigate acute effects of each treatment on regional global brain connectivity (GBC). We leveraged transcriptomic data from the Allen Human Brain Atlas to uncover potential biological and cellular pathways underpinning regional vulnerability to GBC changes induced by each treatment. Interferon-α and anti-TNF therapies both produced differential small-to-medium sized decreases in regional GBC. However, these were observed within distinct brain regions and the regional patterns of GBC changes induced by each treatment did not correlate suggesting independent underlying processes. Further, the spatial distribution of these differential GBC decreases could be captured by multivariate patterns of constitutive regional expression of genes respectively related to: i) neuroinflammation and glial cells; and ii) glutamatergic neurotransmission and neurons. The extent to which each participant expressed patterns of GBC changes aligning with these patterns of transcriptomic vulnerability also correlated with both acute treatment-induced changes in interleukin-6 (IL-6) and, for Interferon-α, longer-term treatment-associated changes in depressive symptoms. Together, we present two transcriptomic models separately linking regional vulnerability to the acute effects of interferon-α and anti-TNF treatments on brain function to glial neuroinflammation and glutamatergic neurotransmission. These findings generate hypotheses about two potential brain mechanisms through which bidirectional changes in peripheral inflammation may contribute to the development/resolution of psychopathology.
Bibliografie:ObjectType-Article-1
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ISSN:0889-1591
1090-2139
1090-2139
DOI:10.1016/j.bbi.2022.03.004