Journal article
Unique pathways downstream of TLR-4 and TLR-7 activation: sex-dependent behavioural, cytokine, and metabolic consequences
- Abstract:
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Introduction: Post-infection syndromes are characterised by fatigue, muscle pain, anhedonia, and cognitive impairment; mechanistic studies exploring these syndromes have focussed on pathways downstream of Toll-like receptor (TLR) 4 activation. Here, we investigated the mechanistic interplay between behaviour, metabolism, and inflammation downstream of TLR-7 activation compared to TLR-4 activation in male and female CD1 mice.
Methods: Animals received either a TLR-4 (LPS; 0.83 mg/kg) or TLR-7 (R848, 5 mg/kg) agonist, or saline, and behaviour was analysed in an Open Field (OF) at 24 h (n = 20/group). Plasma, liver, and prefrontal cortex (PFC) were collected for gene expression analysis at 24 h and 1H-NMR metabolomics.
Results: TLR-4 and TLR-7 activation decreased distance travelled and rearing in the OF, but activation of each receptor induced distinct cytokine responses and metabolome profiles. LPS increased IL-1β expression and CXCL1 in the PFC, but TLR7 activation did not and strongly induced PFC CXCL10 expression. Thus, TLR7 induced sickness behaviour is independent of IL-1β expression. In both cases, the behavioural response to TLR activation was sexually dimorphic: females were more resilient. However, dissociation was observed between the resilient female mice behaviour and the levels of gene cytokine expression, which was, in general, higher in the female mice. However, the metabolic shifts induced by immune activation were better correlated with the sex-dependent behavioural dimorphisms; increased levels of antioxidant potential in the female brain are intrinsic male/female metabolome differences. A common feature of both TLR4 and TLR7 activation was an increase in N-acetyl aspartate (NAA) in the PFC, which is likely be an allostatic response to the challenges as sickness behaviour is inversely correlated with NAA levels.
Discussion: The results highlight how the cytokine profile induced by one PAMP cannot be extrapolated to another, but they do reveal how the manipulation of the conserved metabolome response might afford a more generic approach to the treatment of post-infection syndromes.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 3.3MB, Terms of use)
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- Publisher copy:
- 10.3389/fncel.2024.1345441
Authors
- Funder identifier:
- https://ror.org/03wnrjx87
- Funding agency for:
- Probert, F
- Programme:
- Dorothy Hodgkin Career Development fellow
- Funder identifier:
- https://ror.org/052gg0110
- Funding agency for:
- Dunstan, IK
- Programme:
- Medical Sciences Graduate School Studentship
- Publisher:
- Frontiers Media
- Journal:
- Frontiers in Cellular Neuroscience More from this journal
- Volume:
- 18
- Article number:
- 1345441
- Place of publication:
- Switzerland
- Publication date:
- 2024-02-13
- Acceptance date:
- 2024-02-01
- DOI:
- EISSN:
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1662-5102
- ISSN:
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1662-5102
- Pmid:
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38414751
- Language:
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English
- Keywords:
- Pubs id:
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1670381
- Local pid:
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pubs:1670381
- Deposit date:
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2024-11-11
Terms of use
- Copyright holder:
- Dunstan et al.
- Copyright date:
- 2024
- Rights statement:
- © 2024 Dunstan, McLeod, Radford-Smith, Xiong, Pate, Probert and Anthony. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
- Licence:
- CC Attribution (CC BY)
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