Biology subjects

Heijnen, C. J.

Publications and source records attributed to Heijnen, C. J..

4 recordsLinked to original sources

bioRxiv2026

DRG meningeal tertiary lymphoid structures are regulated by B cells as a pronociceptive locus after peripheral nerve injury

B cell-derived IgG in the dorsal root ganglia (DRG) drives neuropathic pain after peripheral nerve injury (PNI), but the site of B cell organization is unclear. Here, PNI induced leukocyte clusters in the DRG meninges, enveloped by lymphatic endothelium and apposed to high endothelial venules. These clusters resemble tertiary lymphoid structures (TLSs) with germinal center-like features, including germinal center B cells and plasma cells, and follicular dendritic and follicular helper T cells. Single-cell RNA sequencing revealed enrichment of germinal center B cells in the DRG meninges after PNI. Germinal center B cells regulate TLS organization: TLSs were absent after deletion of Ezh2 from germinal center-experienced B cells. Intrathecal CD20 monoclonal antibody to locally deplete B cells also disrupted TLS organization. Conversely, intrathecal B cell transfer to B cell-deficient (muMT) mice was sufficient for TLS organization after PNI. Allodynia did not develop when TLS organization was disordered. Similar TLSs formed in pig DRG after tail docking and in human donors with chronic pain, where B cell receptor clonotype analysis confirmed functional maturity. Together, these data establish that germinal center B cells are required for TLS organization, and that disrupting this process abolishes the development of neuropathic pain after PNI.

neuroscience↗

bioRxiv2025

Autoreactive IgG levels and Fc receptor γ subunit upregulation drive mechanical allodynia after nerve constriction or crush injury

B cells contribute to the development of pain after sciatic nerve chronic constriction injury (CCI) via binding of immunoglobulin G (IgG) to Fc gamma receptors (Fc{gamma}Rs) in the lumbar dorsal root ganglia (DRG) and spinal cord. Yet the contribution of B cells to pain after different types of peripheral nerve injury is uncertain. Using male and female mice, we demonstrate a divergent role for B cell-IgG-Fc{gamma}R signaling underlying mechanical allodynia between CCI, nerve crush (NC), spared nerve injury (SNI), and spinal nerve ligation (SNL). Depletion (monoclonal anti-CD20) or genetic deletion (muMT mice) of B cells prevented development of allodynia following NC and CCI, but not SNI or SNL. In apparent contradiction, circulating levels of autoreactive IgG and circulating immune complexes were increased in all models, though more prominent following NC and CCI. Passive transfer of IgG from SNI donor mice induced allodynia in CCI muMT recipient mice, demonstrating that IgG secreted after SNI is pronociceptive. To investigate why pronociceptive IgG did not contribute to mechanical allodynia after SNI, we evaluated levels of the Fc receptor {gamma} subunit. SNI or SNL did not increase {gamma} subunit levels in the DRG and spinal cord, whereas CCI and NC did, in agreement with B cell-dependent allodynia in these models. Together, the results suggest that traumatic peripheral nerve injury drives secretion of autoreactive IgG from B cells. However, levels of cognate Fc{gamma}Rs are increased following sciatic nerve constriction and crush, but not transection, to differentially regulate pain through the B cell-IgG-Fc{gamma}R axis.

neuroscience↗

bioRxiv2023

Tonic Meningeal Interleukin-10 Upregulates Delta Opioid Receptor to Prevent Relapse to Pain

Chronic pain often alternates between transient remission and relapse of severe pain. While most research on chronic pain has focused on mechanisms maintaining pain, there is a critical unmet need to understand what prevents pain from re-emerging in those who recover from acute pain. We found that interleukin (IL)-10, a pain resolving cytokine, is persistently produced by resident macrophages in the spinal meninges during remission from pain. IL-10 upregulated expression and analgesic activity of {delta}-opioid receptor ({delta}OR) in the dorsal root ganglion. Genetic or pharmacological inhibition of IL-10 signaling or {delta}OR triggered relapse to pain in both sexes. These data challenge the widespread assumption that remission of pain is simply a return to the naive state before pain was induced. Instead, our findings strongly suggest a novel concept that: remission is a state of lasting pain vulnerability that results from a long-lasting neuroimmune interactions in the nociceptive system.

neuroscience↗

bioRxiv2019

PI16 is a non-neuronal regulator of neuropathic pain

Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury model of neuropathic pain increases PI16 protein levels in fibroblasts in DRG meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes trans-endothelial leukocyte migration. In vivo, PI16-/- mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx and increased pain. Its key role in pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=128 HEIGHT=200 SRC=\"FIGDIR/small/696542v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@172f530org.highwire.dtl.DTLVardef@3f62a8org.highwire.dtl.DTLVardef@16606ccorg.highwire.dtl.DTLVardef@1485156_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗