Biology subjects

Horsnell, H. L.

Publications and source records attributed to Horsnell, H. L..

4 recordsLinked to original sources

bioRxiv2026

Immune responses to infection modulate peripheral sympathetic neuron functions

The central nervous system interprets inflammatory signals in the body and directs the modulation of inflammatory responses by reflexively engaging peripheral sympathetic neurons1,2. This includes sympathetic neurons that innervate the spleen, which can regulate immune functions3-5 and modulate inflammation6-8. Yet, it is unclear if neuroimmune interactions involve specialised immunoregulatory sympathetic neurons, and if the immune system can reciprocally regulate peripheral sympathetic neurons to control these responses. Using retrograde tracing and single-cell transcriptomics, we find that spleen-innervating neurons are heterogeneous but do not exhibit a distinct transcriptional program indicative of specialisation for immune communication. However, we report that immune responses induced by pathogens can regulate postganglionic sympathetic neuron functions. Cytokines produced by immune cells downregulate expression of the neurotrophin nerve growth factor in spleen mesenchymal cells, leading to organ-specific sympathetic nerve retraction from the spleen. Concurrently, splenic type I interferon signalling induces inflammatory gene expression in neurons and suppresses neuron excitability. Chemogenetic activation of sympathetic neurons demonstrates an impaired anti-inflammatory capacity in the spleen during infection. These results reveal regulation of sympathetic neuronal functions by the immune system, which could support optimal generation of immune responses against pathogens.

immunology↗

bioRxiv2023

The transcription factor SpiB regulates Fibroblastic Reticular Cell network and CD8+ T cell responses in lymph nodes

Fibroblastic Reticular Cells (FRCs) construct microanatomical niches that support lymph node homeostasis and coordination of immune responses. Transcription factors regulating the functionality of FRCs remain poorly understood. Here we investigate the role of the transcription factor SpiB that is expressed in lymph node FRCs. Conditional ablation of SpiB in FRCs impaired the FRC network in the T cell zone of lymph nodes, leading to reduced numbers of FRCs and altered homeostatic functions including reduced CCL21 and interleukin-7 expression. The size and cellularity of lymph nodes remained intact in the absence of SpiB but the space between the reticular network increased, indicating that although FRCs were reduced in number they stretched to maintain network integrity. Following virus infection, antiviral CD8+ T cell responses were impaired, suggesting a role for SpiB expression in FRCs in orchestrating immune responses. Together, our findings reveal a new role for SpiB as a critical regulator of FRC functions and immunity in lymph nodes.

immunology↗

bioRxiv2022

Podoplanin expression in fibroblasts determines lymph node architecture and adaptive immune function

Lymph nodes are uniquely organised niches for immune interactions. Fibroblastic reticular cells (FRCs) facilitate immune cell communication and regulate immune function by producing growth factors, chemokines and inflammatory cues. Stromal expression of the glycoprotein Podoplanin (PDPN) is required for lymph node development, but the requirement for PDPN signaling in FRCs in adult lymph nodes has not been directly tested. Using a conditional in vivo deletion model PDGFRmGFP{Delta}PDPN, scRNA-seq revealed that PDPN deletion increased inflammatory signalling in lymph nodes and disrupted stromal-immune cells crosstalk in steady state and during adaptive immune responses. We confirmed that PDPN/CLEC-2 signaling in FRCs switches transcriptional states and alters expression of immune related genes. We conclude that Podoplanin expression impacts the immunoregulatory properties of fibroblastic stroma in lymph nodes and is a key transcriptional regulator of fibroblast function in lymph nodes. Summary: Podoplanin expression regulates the immunoregulatory properties of fibroblastic stroma in lymph nodes

immunology↗

bioRxiv2021

Mechanical Forces during Lymph Node Expansion Govern Fibroblastic Reticular Network Remodeling

Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular physical properties, collectively determining tissue mechanics of lymph nodes, an immunologically-relevant, adult mammalian tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive tissue expansion upon immune challenge. We find that following immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds. We determine that CLEC-2/podoplanin signalling regulates the cell surface mechanics of fibroblasts, permitting cell elongation and interdigitation through expedited access to plasma membrane reservoirs. Increased tissue tension through the stromal meshwork gates the initiation of fibroblast proliferation, restoring homeostatic cellular ratios and tissue structure through expansion.

biophysics↗