Sung, C. C. | Search bioRxiv

bioRxiv2026

A regulatory TRIF/IL-1R1 axis controls T-dependent IgA production in the intestines

Mucosal IgA is critical for controlling the microbiota and preventing pathogenic infection of the epithelium. The innate signals that regulate the generation of IgA remain poorly defined. Here, we identified TRIF and IL-1R1 as immune checkpoints for intestinal IgA production. In the absence of infection, Trif-/- and Il1r1-/- mice exhibited markedly elevated stool IgA and IgA-bound commensals. We show that IL-1R1 restricts IgA class-switching in a B cell-intrinsic manner, while TRIF acts extrinsically of B cells and shapes the Peyers patch microenvironment. Loss of either Trif or Il1r1 enhanced retinoic acid metabolism and allowed premature Ccnd3 upregulation in naive B cells, favoring both IgA class-switching and differentiation into germinal center B cells. During oral vaccination, the absence or blockade of the TRIF/IL-1R1 pathway increased antigen-specific IgA production without affecting seric antigen-specific IgG levels. These findings unveil novel and local signaling targets to promote robust antigen-specific mucosal immunity.

immunology↗

bioRxiv2023

Piezo1 agonist restores meningeal lymphatic vessels, drainage, and brain-CSF perfusion in craniosynostosis and aged mice

Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood. We report that raised intracranial pressure and diminished CSF flow in craniosynostosis mouse models associates with pathological changes to meningeal lymphatic vessels that affect their sprouting, expansion, and long-term maintenance. We also show that craniosynostosis affects CSF circulatory pathways and perfusion into the brain. Further, craniosynostosis exacerbates amyloid pathology and plaque buildup in Twist1+/-:5xFAD transgenic Alzheimers disease models. Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.

neuroscience↗