Biology subjects

Dochnal, S.

Publications and source records attributed to Dochnal, S..

3 recordsLinked to original sources

bioRxiv2025

Neutrophil-neuronal crosstalk drives arthritis-induced pain

Pain in rheumatoid arthritis (RA) often persists despite effective control of inflammation, suggesting distinct mechanisms driving nociception. In both patients and animal models, pain severity does not strongly correlate with the degree of inflammation1,2. Sensory neurons, with cell bodies located in the dorsal root ganglia (DRG), innervate peripheral tissues, including joints, and transmit pain signals to the central nervous system. Crosstalk between sensory neurons and immune cells occurs at all of these sites. While sensory neurons can be directly activated by immune mediators, it remains unclear whether pain-like behaviour in antibody-induced arthritis models arises independently of immune cell activity, or which immune cell populations and mediators are required to activate pronociceptive mechanisms. Through temporal profiling of the CAIA joint-DRG transcriptomic axis, we identified SEMA4D and OSM signalling as candidate molecular mediators of neutrophil-neuron communication and neuronal sprouting. The joint-DRG atlas also revealed persistent changes in the fibroblast-immune cellular composition of the joint, along with molecular changes in DRG neurons. We showed that mechanical and cold hypersensitivity, as well as sprouting of CGRP+ nociceptive fibers in synovial tissue of mice with collagen antibody-induced arthritis (CAIA), require neutrophils but not macrophages. Analysis of publicly available datasets showed that neutrophils from the synovium of RA patients express high levels of SEMA4D and OSM, and corresponding expression of their receptors, PLEXINB1 and OSMR, in human DRG neurons, underscoring the translational relevance of this axis. Both murine and human-derived DRG neurons sprout in response to OSM. Our findings demonstrate that neutrophils produce molecules that act as cues for nociceptor sensitization and structural remodelling. Targeting these molecules could improve the efficacy of RA treatments by reducing pain while simultaneously preventing disease progression.

immunology↗

bioRxiv2021

PML-Dependent Memory of Type I Interferon Treatment Results in a Restricted Form of HSV Latency

Herpes simplex virus (HSV) establishes latent infection in long-lived neurons. During initial infection, neurons are exposed to multiple inflammatory cytokines but the effects of immune signaling on the nature of HSV latency is unknown. We show that initial infection of primary murine neurons in the presence of type I interferon (IFN) results in a form of latency that is restricted for reactivation. We also found that the subnuclear condensates, promyelocytic leukemia-nuclear bodies (PML-NBs), are absent from primary sympathetic and sensory neurons but form with type I IFN treatment and persist even when IFN signaling resolves. HSV-1 genomes colocalized with PML-NBs throughout a latent infection of neurons only when type I IFN was present during initial infection. Depletion of PML prior to or following infection did not impact the establishment latency; however, it did rescue the ability of HSV to reactivate from IFN-treated neurons. This study demonstrates that viral genomes possess a memory of the IFN response during de novo infection, which results in differential subnuclear positioning and ultimately restricts the ability of genomes to reactivate.

immunology↗

bioRxiv2020

Neuronal Hyperexcitability is a DLK-dependent Trigger of HSV-1 Reactivation that can be Induced by IL-1

Herpes Simplex Virus (HSV) establishes a latent infection in neurons and periodically reactivates to cause disease. The neuronal stimuli that trigger HSV reactivation have not been fully elucidated. Here we demonstrate that HSV reactivation can be induced by neuronal hyperexcitability. Neuronal stimulation-induced reactivation was dependent on voltage-gated ion and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, demonstrating that neuronal activity is required for reactivation. Hyperexcitability-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and progressed via an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1{beta} induces neuronal hyperexcitability and is released under conditions of stress and fever; both known triggers of clinical HSV reactivation. IL-1{beta} induced histone phosphorylation in sympathetic neurons, and importantly HSV reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.

microbiology↗