Gardner-Stephen, K. | bioRxiv Science

bioRxiv2025

Macrophages drive inguinal fat pad and lymph node remodelling in response to peripheral inflammation.

Adaptive immune responses are intensely energy-dependent and rely on a local source of fuel-producing molecules which have been proposed to be derived from fat pads in which mammalian lymph nodes are embedded. However, the trigger for their release has not been identified. Here we demonstrate that cutaneous inflammation is directly correlated with rapid atrophy of perinodal fat pads and increase in embedded lymph node size. We further demonstrate that the fat pad atrophy is associated with influx of a CCR2-independent, lipid metabolising, macrophage population. Macrophage depletion ameliorates fat pad atrophy, and lymph node expansion, downstream of inflamed sites. Our data therefore identify peripheral inflammation as an antigen-independent trigger of downstream fat pad and lymph node remodelling and contributes to the release of essential nutrients to drive the energetic requirements of the adaptive immune response.

immunology↗

bioRxiv2024

Anhedonic behaviour in a TLR7-driven neuroinflammation mouse model is associated with impaired thalamostriatal signalling and immune cell ingress into the brain

Inflammation is implicated in 25% of depression cases, yet limited access to human brain for mechanistic studies and scarce translational models have hindered the identification of neural circuits linking systemic inflammation to depressive symptoms such as reduced motivation and anhedonia. Leveraging both clinical and pre-clinical approaches, we combined neuroimaging in individuals with psoriatic disease, a systemic inflammatory condition frequently associated with depression, with neurophysiological, behavioural and immunological studies in a psoriasis mouse model exhibiting neuroinflammation. We found that increased inflammation had a robust association with both depression and fatigue in individuals with psoriatic disease. Across species, we found that inflammatory signalling disrupts thalamostriatal circuitry, a key component of the motivational network. In humans, functional connectivity between thalamus and ventral striatum correlated with depressive and fatigue-related symptoms. In mice, psoriasis-like inflammation produced impaired thalamostriatal synaptic transmission accompanied by anhedonia and motivation-related behavioural deficits, together with glial activation and immune-cell infiltration. These cross-species findings identify the thalamostriatal circuit as a conserved neuroinflammatory hotspot involved in depression and highlight it as a potential therapeutic target.

neuroscience↗