Biology subjects

Cole, J. J.

Publications and source records attributed to Cole, J. J..

4 recordsLinked to original sources

bioRxiv2025

Neuroinflammation driven by TLR7 activation in mice results in a global inflammatory response driving circuit-specific changes in neuronal gene expression

Interactions between the brain and immune system play a key role in the aetiology of brain disorders, with inflammation emerging as a potential causal factor in subsets of major depressive disorder, particularly those resistant to treatment. The causal mechanisms through which immune activation can drive depressive symptoms remain elusive, limiting the ability to develop new targeted therapies. Using a mouse model of neuroinflammation, involving a TLR7/8 agonist, we found central and systemic inflammation alongside anhedonia-like behaviours, altered thalamostriatal signalling and infiltration of peripheral immune cells into the brain. Here, we sought to use combined whole-brain transcriptome and spatial transcriptomics approaches to determine whether Aldara-driven neuroinflammation resulted in consistent immune and neurobiological changes throughout the brain. We found evidence of strong immune activation throughout the brain, with astrocytes displaying a strong inflammatory profile that was relatively uniform throughout. However, we found that this global inflammatory signal led to regionally-specific changes in gene expression, particularly reduced expression of genes associated with synaptic function in brain areas underlying mood and anxiety, such as ventral striatum and amygdala. Our data suggest potential mechanisms through which astrocytes regulate neuronal function in response to inflammation.

neuroscience↗

bioRxiv2024

Eosinophils promote monocyte to macrophage differentiation and anti-bacterial immunity

Chemokine receptors control cell migration within the body. Here we reveal a novel interaction between eosinophils and monocytes in the bone marrow, indirectly controlled by the atypical chemokine receptor ACKR2. We demonstrate that ACKR2 maintains eosinophil levels within the bone marrow by scavenging CCL11. In the absence of ACKR2, elevated CCL11 leads to increased egress of eosinophils from the bone marrow into the bloodstream. As a result, eosinophil and monocyte interactions are reduced within the bone marrow niche, leading to changes in monocyte gene expression. Monocytes from ACKR2-/- mice are recruited to the tissues but are fundamentally altered in their ability to differentiate into macrophages, in the lung, peritoneal cavity and cavity wall. Bacterial elimination is impaired in ACKR2-/- mice during peritoneal infection. ACKR2 is therefore a key regulator of eosinophil-driven monocyte education in the bone marrow, required for full monocyte differentiation and macrophage function within the tissues.

immunology↗

bioRxiv2024

Lung structural cell dynamics are altered by influenza virus infection experience leading to rapid immune protection following viral re-challenge

Lung structural cells, including epithelial cells and fibroblasts, form barriers against pathogens and trigger immune responses following infections such as influenza A virus. This response leads to the recruitment of innate and adaptive immune cells required for viral clearance. Some of these recruited cells remain within the lung following infection and contribute to enhanced viral control following subsequent infections. There is growing evidence that structural cells can also display long-term changes following infection or insults. Here we investigate long-term changes to mouse lung epithelial cells, fibroblasts, and endothelial cells following influenza virus infection and find that all three cell types maintain an imprint of the infection, particularly in genes associated with communication with T cells. Lung epithelial cells from IAV-infected mice display functional changes by more rapidly controlling influenza virus than cells from naive animals. This rapid anti-viral response and increased expression of molecules required to communicate with T cells demonstrates sustained and enhanced functions following infection. These data suggest lung structural cells could be effective targets for vaccines to boost durable protective immunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/604410v5_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@2774e0org.highwire.dtl.DTLVardef@6a39e6org.highwire.dtl.DTLVardef@1ff5863org.highwire.dtl.DTLVardef@103df12_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LILung epithelial cells, fibroblasts, and blood endothelial cells maintain an inflammatory imprint of influenza A virus (IAV) infection for at least 40 days post-infection. C_LIO_LIIn vivo re-infection leads to a more spatially restricted anti-viral response compared to primary IAV-infected animals. C_LIO_LIT cells are not required for enhanced viral control early after re-infection in vivo C_LIO_LIEx vivo lung epithelial cells from IAV-infected mice more rapidly control IAV than cells from naive animals in the absence of immune cells. C_LI

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↗