Biology subjects

Cutforth, T.

Publications and source records attributed to Cutforth, T..

4 recordsLinked to original sources

bioRxiv2026

Th17 effector cytokines induce shared and distinct microglial and endothelial cell responses in post-streptococcal encephalitis

Group A Streptococcus (GAS) infections can lead to neuropsychiatric sequelae in children, yet the mechanisms driving post-infectious brain pathology remain poorly defined. In a mouse disease model, Th17 lymphocytes induce microglial activation, blood-brain barrier (BBB) dysfunction, and neural circuit impairment; however, the transcriptional programs underlying these effects, and the specific Th17-derived cytokines involved are unclear. Using mouse genetics, single-cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory gene programs in microglia and brain endothelial cells (BECs), accompanied by downregulation of BBB-associated transcripts in BECs. Spatial transcriptomic analyses reveal that GAS-responsive microglia are enriched near infiltrating T cells. Several chemokines upregulated in microglia following GAS infection in mice are elevated in sera from affected patients. Conditional ablation of GM-CSF in CD4+ T cells partially attenuates microglial chemokine gene expression, but does not restore BBB integrity. Neutralization of IL-17A partially rescues BBB transcriptional changes in BECs and reduces microglial chemokine expression; however, compensatory peripheral immune responses associated with persistent infection exacerbate BBB disruption. In contrast, microglia/macrophage-specific deletion of IL-17 receptor A partially rescues BBB deficits following GAS infection. Together, these findings identify IL-17A-IL-17RA signaling in microglia as a critical driver of BBB dysfunction after GAS infections.

neuroscience↗

bioRxiv2023

Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis

Group A Streptococcus (GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown. Using single-cell RNA sequencing and spatial transcriptomics, we found that ECs downregulate BBB genes and microglia upregulate interferon-response, chemokine and antigen-presentation genes after GAS infections. Several microglial-derived chemokines were elevated in patient sera. Administration of a neutralizing antibody against interleukin-17A (IL-17A), but not ablation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, partially rescued BBB dysfunction and microglial expression of chemokine genes. Thus, IL-17A is critical for neuropsychiatric sequelae of GAS infections and may be targeted to treat these disorders.

neuroscience↗

bioRxiv2022

Mural norrin/β-catenin signaling regulates Lama2 expression to promote neurovascular unit assembly

Neurovascular unit (NVU) assembly and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are critical for these processes, yet which signaling pathway(s) regulate their expression remains unknown. Here we show that mural cells have active Norrin/{beta}-catenin signaling during central nervous system development. Bulk RNA sequencing and validation using P10 and P14 wild-type versus Apcdd1-/- retinas reveal that Lama2 (Laminin-2 chain) mRNA and protein levels are increased in mutant vasculature undergoing higher Norrin/{beta}-catenin signaling. Mural cells are the main source of Lama2, and {beta}-catenin activation induces Lama2 expression in mural cells in vitro. Markers of mature astrocytes including Aquaporin-4 (a water channel in astrocyte endfeet) and Integrin-6 (a laminin receptor) are upregulated in Apcdd1-/- retinas following higher Lama2 vBM deposition. Thus, the Norrin/{beta}-catenin pathway regulates Lama2 expression in mural cells to promote NVU assembly and neurovascular barrier maturation. SUMMARYBiswas et al., demonstrate that Norrin/{beta}-catenin signaling is active in CNS mural cells and regulates Lama2 deposition in the vascular basement membrane, promoting neurovascular unit assembly and blood-CNS barrier maturation.

developmental biology↗

bioRxiv2022

Interaction of an α-synuclein epitope with HLA-DRB1*15:01 initiates early enteric features of Parkinson's disease in humanized mice

Enteric symptoms, including constipation, are hallmarks of prodromal Parkinsons disease (PD) that can appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific -synuclein-(-syn)-derived epitopes. One epitope, -syn32-46, binds with strong affinity to the HLA-DRB1*15:01 allele implicated in autoimmune diseases. We report that -syn32-46 immunization in a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation leading to loss of enteric neurons, damage of enteric dopaminergic neurons, constipation and weight loss. -Syn32-46 immunization activates innate and adaptive immune gene signatures in the gut and induces changes in CD4+ TH1/ TH17 transcriptome that resemble tissue resident memory cells found in mucosal barriers during inflammation. Depletion of CD4+, but not CD8+, T cells partially rescues enteric neurodegeneration. Therefore, interaction of -syn32-46 and HLA-DRB1*15:0 is critical for gut inflammation and CD4+ T cell-mediated loss of enteric neurons in humanized mice, suggesting potential mechanisms of prodromal enteric PD. HIGHLIGHTS AND eTOC BlurbO_LI-syn32-46 immunization of an HLA-DRB1*15:01 mouse triggers weight loss and constipation. C_LIO_LI-syn32-46 immunizations induce gut inflammation, loss of enteric neurons and damage to dopaminergic neurons. C_LIO_LI-syn32-46 immunization induces innate and adaptive immune responses in the gut. C_LIO_LIDepletion of CD4+, but not CD8+, T cells partially rescues enteric neural loss. C_LIO_LIAn interaction between -syn32-46 and HLA-DRB1*15:01 is critical for this model of prodromal PD. C_LI Parkinsons disease (PD) patients exhibit elevated number of circulating T cells that recognize -synuclein-(-syn)- epitopes, particularly during early disease stages. One epitope, -syn32-46, interacts with the HLA-DRB1*15:01; however, its role in PD pathogenesis remains unknown. Garretti et al. show that -syn32-46 immunization of a mouse expressing HLA-DRB1*15:01 triggers intestinal inflammation, a loss of enteric neurons, constipation and weight loss, suggesting a critical role for -syn autoimmunity in HLA-DRB1*15:01 carriers in prodromal PD.

neuroscience↗