Biology subjects

Herbath, M.

Publications and source records attributed to Herbath, M..

6 recordsLinked to original sources

bioRxiv2026

Ethmoid bone marrow region modulates lymphoid activation and differentiation with distinct myeloid profile in neuroinflammation

The skull bone marrow axis has recently emerged as an important source of immune cells during neuroinflammation, including in the experimental autoimmune encephalomyelitis (EAE) , the mouse model of multiple sclerosis. The cribriform plate bone marrow (cpBM), is a portion of the ethmoid bone of the skull of mice, and is positioned next to nasal regions. At the cribriform plate olfactory nerves pass through the skull and recent evidence supports that it represents an important immune niche with links to CSF outflow and connections to cpBM. Previous data supports cellular composition of the ethmoid bone marrow in mice is altered in neuroinflammation suggesting it senses inflammatory cues, but the exact nature of these changes is still unclear. Here using scRNAseq and flow cytometry of the ethmoid bone marrow region we test how the region responds to EAE. In addition we also compare the cpBM region with systemic bone marrow in the femur to understand region specific differences. We report that neuroinflammation creates a regulatory response at these sites and implicates the cpBM in controlling these effects. A better understanding of the cribriform niche may offer new treatments for neuroinflammatory disease

immunology↗

bioRxiv2026

A New aspect of the pathology of brain tuberculosis: Mycobacterium tuberculosis infects and alters human neural progenitor cells

Brain tuberculosis remains associated with high mortality, and many survivors exhibit cognitive impairments. Progress in understanding the disease is hindered by the lack of human models. In this study, human neural organoids were infected, revealing that a subpopulation of neural progenitor cells (NPCs) is directly infected by apoptotic cell receptors expressed by NPCs, mediating bacterial uptake. Phagocytosed bacteria were localized in late endosomes, lysosomes, and the cytoplasm. Cytoplasmic bacteria frequently formed cords, indicating limited control of bacterial expansion. Immunostaining demonstrated that infected NPCs produce a type I interferon (IFN) response, corroborated by increased expression of type I IFN and IFN-regulated genes detected by RNA sequencing. Pathways related to innate immune response, cell death, and proliferation were also activated following Mycobacterium tuberculosis (Mtb) uptake by NPCs. The addition of color-coded microglia and monocytes to 3D neural organoids and NPCs revealed cross-infection of NPCs and other phagocytes by Mtb, suggesting a mechanism by which NPCs may access the bacteria. Infection of NPCs resulted in increased cell death, inhibition of neural differentiation, and reduced proliferation, effects that were partially mitigated by anti-IFN treatment. Differentiated neurons were not infected. These findings indicate that brain organoids and NPC-based in vitro platforms provide a novel approach for studying brain tuberculosis. Decreased NPC function may contribute to brain tuberculosis-induced cognitive disease.

immunology↗

bioRxiv2026

Structural and Immunological Alterations at the Human Cribriform Plate in Streptococcus pyogenes Meningitis: A Case Study

Streptococcus pyogenes or group A Streptococcus (GAS) meningitis is a rare but deadly infection with a high mortality. Its mechanisms of invasion are unknown, but it has been proposed to enter either through the cribriform plate olfactory nerve bundles or the blood brain barrier. Knowledge of how GAS impacts the cribriform plate olfactory nerves can help us better understand GAS pathogenesis and invasion, as well as how it impacts the olfactory nerve bundles. Here we present the case of a 39-year-old otherwise healthy man who presented to the local emergency department with altered mental status and expired the following day. Neuropathologic examination revealed bacterial leptomeningitis; blood and cerebrospinal fluid cultures both grew Streptococcus pyogenes. Examination of the cribriform plate was notable for perineural accumulation of GAS around certain olfactory nerve bundles. The accumulation around nerves seems to be random and not correlated to size. Nerves that are impacted by GAS as well as nerves that are not impacted display similar levels of gliosis markers GFAP and podoplanin. Neuropeptide Y, a neuropeptide that implicated in neuro-proliferation and hunger was found to colocalize with CD68 positive immune cells within the nasal epithelium, leading to speculations of its involvement in the inflammatory profile during this case of GAS meningitis. Cribriform plate skull channels had undergone width expansion within the patient, pointing towards local bone marrows involvement during infections. These findings are essential to better understanding the human cribriform plates role in CNS immune response and drainage.

neuroscience↗

bioRxiv2026

Cribriform Plate Microenvironment Assembles a Suppressive Myeloid Network during EAE-induced Neuroinflammation

During neuroinflammation, CD11c+CD11b+ myeloid cells accumulate at the cribriform plate, a key cerebrospinal fluid (CSF) and antigen outflow site in mice. At this site, podoplanin (PDPN)-expressing cells, including lymphatic vessels and meningeal layers, expand to create a distinct drainage microenvironment. In this study we sought to characterize myeloid cells which populate this region using a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE). Utilizing a combination of immunohistochemistry, flow cytometry, and scRNAseq, we report that macrophages and dendritic cells (DCs) from this region display unique expressional signatures related to tolerance, cell death, and reduced inflammatory profile. Together this data supports that myeloid retention at the cribriform plate and olfactory bulb meninges promotes a local immunosuppressive environment.

immunology↗

bioRxiv2023

Dual role of Vascular Endothelial Growth Factor-C (VEGF-C) in post-stroke recovery

Using a mouse model of ischemic stroke, this study characterizes stroke-induced lymphangiogenesis at the cribriform plate (CP). While blocking CP lymphangiogenesis with a VEGFR-3 inhibitor improves stroke outcome, administration of VEGF-C induced larger brain infarcts. AbstractCerebrospinal fluid (CSF), antigens, and antigen-presenting cells drain from the central nervous system (CNS) into lymphatic vessels near the cribriform plate and dural meningeal lymphatics. However, the pathological roles of these lymphatic vessels surrounding the CNS during stroke are not well understood. Using a mouse model of ischemic stroke, transient middle cerebral artery occlusion (tMCAO), we show that stroke induces lymphangiogenesis near the cribriform plate. Interestingly, lymphangiogenesis is restricted to lymphatic vessels at the cribriform plate and downstream cervical lymph nodes, without affecting the conserved network of lymphatic vessels in the dura. Cribriform plate lymphangiogenesis peaks at day 7 and regresses by day 14 following tMCAO and is regulated by VEGF-C/VEGFR-3. These newly developed lymphangiogenic vessels transport CSF and immune cells to the cervical lymph nodes. Inhibition of VEGF-C/VEGFR-3 signaling using a blocker of VEGFR-3 prevented lymphangiogenesis and led to improved stroke outcomes at earlier time points but had no effects at later time points following stroke. Administration of VEGF-C after tMCAO did not further increase post-stroke lymphangiogenesis, but instead induced larger brain infarcts. The differential roles for VEGFR-3 inhibition and VEGF-C in regulating stroke pathology call into question recent suggestions to use VEGF-C therapeutically for stroke.

immunology↗

bioRxiv2020

Neuroinflammation alters the phenotype of lymphangiogenic vessels near the cribriform plate.

Meningeal lymphatic vessels residing in the dural layer surrounding the dorsal regions of the brain, basal regions, and near the cribriform plate have all been implicated in the management of neuroinflammation and edema. Interestingly, only the lymphatic vessels near the cribriform plate undergo functional lymphangiogenesis in a mouse model of Multiple Sclerosis, suggesting these particular lymphatics uniquely undergo dynamic changes in response to neuroinflammation and may have distinct access to pro-lymphangiogenic factors in the CNS. However, it is unknown if these newly formed lymphangiogenic vessels are functionally similar to steady-state or if they have any other functional changes during neuroinflammation. In this study, we generated a novel protocol to isolate lymphatic endothelial cells from the cribriform plate for single cell analysis. We demonstrate that neuroinflammation-induced lymphangiogenic vessels undergo unique changes, including the capture of CNS-derived antigens, upregulation of adhesion and immune-modulatory molecules to interact with dendritic cells, and display IFN-{gamma} dependent changes in response to the microenvironment. Single-cell trajectory analysis showed that cribriform plate lymphangiogenic vessels are post-proliferative and not generated from trans-differentiation of myeloid cells. Additionally, we show that these lymphangiogenic vessels have access to a CSF reservoir, express the water pore Aquaporin-1, and may have direct access to the CSF due to gaps in the arachnoid epithelial layer separating the dura from the subarachnoid space. These data characterize cribriform plate lymphatics and demonstrate that these vessels are dynamic structures that engage in leukocyte interactions, antigen sampling, and undergo expansion to drain excess fluid during neuroinflammation. Neuroinflammation not only induces efficient drainage of CSF but also alters the functions of lymphatic vessels near the cribriform plate.

immunology↗