Unique pathways downstream of TLR-4 and TLR-7 activation: sex-dependent behavioural, cytokine, and metabolic consequences 2024 Dunstan et al

[In mice]

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.

Open access, https://www.frontiersin.org/articles/10.3389/fncel.2024.1345441/full

 

It's nice to see work that reveals the complexity of the immune response, and that there are sex differences. Too many papers seem to focus on one chemical reaction and then claim that it explains everything for everyone.

 

Yes, this looks interesting. Studies of normal control mechanisms in mice form a bedrock for understanding human mechanisms. It is the study of putative disease pathogenesis that animal models are so misleading for.

If TLR-7 induces brain changes without raising IL-1beta and that is sex dependent I think it may point to a whole range of similar heterogeneities in 'danger signalling' one of which might be critical for ME.

 

Decided I'd try to flag this up to NIH i.e. potential research area.
https://twitter.com/user/status/1763702427939737915

 

Who would you study this further? In humans? In humans with ME/CFS? How would you go about it as someone who funds ME research? Thank you!

 

I guess the usual way - look for the signal in the disease and see what inhibitors do. There may be TLR-7 inhibitors already. Whether you need to do animal studies first would depend on the detailed logistics I think.