Biology subjects

Herbert, D.

Publications and source records attributed to Herbert, D..

9 recordsLinked to original sources

bioRxiv2026

Sensory neurons shape γδ T cell effector programs to control Psoriasiform Inflammation.

Psoriasis is a chronic autoimmune skin disorder marked by IL-17 producing gamma delta T cell ({gamma}{delta}T17) and pruritus, but immunoregulatory roles of itch-inducing neurons in this context remain unclear. This study addressed whether non-peptidergic (NP) afferents bearing the Mas-related G protein-coupled receptor D (MrgprD/NP1) and MrgprA3/NP2 subsets had differential effects on psoriasiform immunopathology. Data show human NP1 and NP2 neurons basally expressed an array of pattern recognition and cytokine receptor genes and psoriatic human skin had a profound dysregulation of neuropeptides and their receptors. In mice, imiquimod (IMQ) application reduced the density of MrgprD+ skin afferents, whereas NP1 neuron ablation exacerbated IMQ-induced disease. Strikingly, NP1 activation using either optogenetics or {beta}-alanine before IMQ exposure significantly reduced epidermal thickness, psoriatic clinical score and {gamma}{delta}T17 cell accumulation. In stark contrast, NP2 activation increased the numbers of {gamma}{delta}T17 cells that co-expressed amphiregulin (Areg) and exacerbated IMQ-driven skin pathology. Instead, pre-emptive NP1 stimulation shifted {gamma}{delta} T cell profiles away from being IL-17 and Areg dominant to IL-13+ {gamma}{delta} T cells expressing the transcription factor GATA3 accompanied by IL-10 secretion. Importantly, IL-10 signaling blockade reversed NP1-mediated suppression of IMQ-induced dermatitis. These data show that inflammatory skin disease can be distinctly modulated by sensory neuron subsets.

immunology↗

bioRxiv2025

CD14 plays a critical role in pain and inflammation across multiple models of post-traumatic osteoarthritis

Inflammation is a primary driver of osteoarthritis (OA), and no therapies exist to halt or delay disease progression or substantially ameliorate the chronic pain, inflammation and disability that are characteristic of disease. Soluble CD14 (sCD14), a co-factor that enhances inflammatory toll-like receptor signaling, is present in synovial fluid in patients with OA and positively associates with joint space narrowing, synovial macrophage content, and pain. In this study, we show that increased sCD14 within human synovial fluid correlates with joint effusion volume and increased knee hyperalgesia. Next, we evaluated CD14 as a potential therapeutic target in three pre-clinical models of post traumatic OA (PTOA), using both genetic deficiency and pharmacologic blockade to modulate its activity. We demonstrate that deficiency or blockade of CD14 results in significant protection from increased evoked pain behaviors and from OA driven mobility impairments (i.e. decreased cage activity) across models that differ in severity, and across male and female cohorts. Using flow cytometry, single cell transcriptomics, and spatial proteomics, we further show that CD14-deficiency drastically influences the local synovial inflammatory landscape post-injury, reducing monocyte and macrophage populations and modulating local fibroblast populations. Targeting CD14 via genetic deficiency or therapeutic blockade revealed no substantial protection, but no worsening, of cartilage degeneration. Ultimately, our results provide strong support that targeting synovial inflammation through blockade of CD14 can safely ameliorate OA pain and disability after a pre-disposing injury. One Sentence SummaryThe study demonstrates the key role of CD14 in pain, mobility loss, and inflammation in PTOA, and demonstrates the therapeutic potential of CD14 blockade for OA pain relief.

immunology↗

bioRxiv2025

TRPV1+ neurons promote cutaneous immunity against Schistosoma mansoni.

Immunity against skin-invasive pathogens requires mechanisms that rapidly detect, repel or immobilize the infectious agent. While bacteria often cause painful cutaneous reactions, host skin invasion by the human parasitic helminth Schistosoma mansoni often goes unnoticed. This study investigated the role of pain-sensing skin afferents that express the ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) in the detection and initiation of skin immunity against S. mansoni. Data show that mice infected with S. mansoni have reduced behavioral responses to painful stimuli and sensory neurons exposed from infected mice have significantly less calcium influx and neuropeptide release in response to the TRPV1 agonist capsaicin. Using both gain- and loss-of-function approaches, data show that TRPV1+ neurons are critical regulators of S. mansoni survival during migration from the skin into the pulmonary tract. Moreover, TRPV1+ neurons were both necessary and sufficient to promote proliferation and cytokine production from dermal {gamma}{delta} T cells as well as neutrophil and monocyte skin accumulation post-infection. These results suggest a model in which S. mansoni may have evolved to inhibit TRPV1+ neuron activation as a countermeasure that limits IL-17-mediated inflammation, facilitating systemic dissemination and chronic parasitism. One sentence summaryThe parasitic helminth Schistosoma mansoni averts IL-17-dependent protective immunity by suppressing skin-innervating TRPV1+ neurons.

immunology↗

bioRxiv2024

A type 1 immune-stromal cell network mediates disease tolerance and barrier protection against intestinal infection

Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here we demonstrate that rapid induction of IFN{gamma} signaling coordinates a multi-cellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFN{gamma} production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFN{gamma} acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFN{gamma} sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response had limited impact on parasite burden, indicating that IFN{gamma} supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodelling. HIGHLIGHTSO_LIType 1 immunity is required for disease tolerance to tissue-invasive infection. C_LIO_LIGut-resident CD8+ T cells produce IFN{gamma} in an antigen-independent, yet microbiota-dependent manner. C_LIO_LIIFN{gamma} signaling recruits neutrophils in a cell-extrinsic manner to limit helminth-induced tissue injury. C_LIO_LIDirect sensing of IFN{gamma} by intestinal stroma is essential to limit tissue damage and maintain gut motility during infection. C_LI

immunology↗

bioRxiv2021

Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host

Helminth infections, including hookworms and Schistosomes, can cause severe disability and death. Infection management and control would benefit from identification of biomarkers for early detection and prognosis. While animal models suggest that Trefoil Factor Family proteins (TFF2 and TFF3) and interleukin-33 (IL-33) -driven type 2 immune responses are critical mediators of tissue repair and worm clearance in the context of hookworm infection, very little is known about how they are modulated in the context of human helminth infection. We measured TFF2, TFF3, and IL-33 levels in serum from patients in Brazil infected with Hookworm and/or Schistosomes, and compared them to endemic and non-endemic controls. TFF2 was specifically elevated by Hookworm infection, not Schistosoma or co-infection. This elevation was more strongly correlated with age than with worm burden. To determine if this might apply more broadly to other species or regions, we measured TFFs and cytokine levels in both the serum and urine of Nigerian school children infected with S. haematobium. We found that serum levels of TFF2 and 3 were reduced by infection, but urine cytokine levels were increased (IL-1{beta}, TNF, IL-13, and IL-10). Finally, to determine if TFF2 and 3 might have immunosuppressive effects, we treated stimulated or unstimulated PMBCs with recombinant human TFF2 or TFF3 and measured proinflammatory cytokine levels. We found that rhTFF2, but not rhTFF3, was able to suppress TNF alpha and IFN gamma release from stimulated human PMBCs. Taken together, these data support a role for TFF proteins in human helminth infection. Author SummaryBillions of people are infected with parasitic helminths across the globe, especially in resource poor regions. These infections can result in severe developmental delay, disability, and death. Adequate management of helminth infection would benefit from the identification of host biomarkers in easily obtained samples (e.g. serum or urine) that correlate to infection state. Our goal was to determine if specific proteins involved in tissue repair and immune modulation are altered by infection with specific helminth species in Brazil (hookworm) or Nigeria (blood fluke). One of these proteins, Trefoil Factor 2 (TFF2), was elevated in the serum of hookworm infected individuals, and decreased in the serum of blood fluke infected children. In the blood fluke-infected children, there were also significant increases in pro-inflammatory cytokines in the urine, where the eggs burst from host tissue. Further, in laboratory experiments, Trefoil Factor 2 reduced the release of pro-inflammatory cytokines from human blood cells. This suggests that at high levels TFF2 may suppress inflammation and could serve as a biomarker for infection or treatment efficacy.

immunology↗

bioRxiv2020

High-resolution temporal transcript profiling during Arabidopsis thaliana gynoecium morphogenesis uncovers the chronology of gene regulatory network activity and reveals novel developmental regulators

The gynoecium is the most complex organ formed by the flowering plants. It encloses the ovules, provides a surface for pollen contact and self-incompatibility reactions, allows pollen tube growth and, post fertilization, and develops into the fruit. Consequently, the regulation of gynoecium morphogenesis is complex and appropriate timing of this process in part determines reproductive success. However, little is known about the global control of gynoecium development, even though many regulatory genes have been characterized. Here, we characterized dynamic gene expression changes using laser-microdissected gynoecium tissue from four developmental stages in Arabidopsis. We provide a high-resolution map of global expression dynamics during gynoecium morphogenesis and link these to the gynoecium interactome. We reveal groups of genes acting together early and others acting late in morphogenesis. Clustering of co-expressed genes enables comparisons between the leaf, shoot apex, and gynoecium transcriptomes allowing the dissection of common and distinct regulators. Furthermore, our results lead to the discovery of the LESSER FERTILITY1-4 (LEF1-4) genes, which, when mutated, lead to impaired gynoecium expansion, illustrating that global transcriptome analyses reveal yet unknown developmental regulators. Our data show that highly interacting proteins, such as SEPALLATA3, AGAMOUS, and TOPLESS are expressed more evenly during development, but switch interactors in time, whereas stage-specific proteins have only few interactors. Our analysis connects specific transcriptional regulator activities, protein interactions, and underlying metabolic processes towards the development of a dynamic network model for gynoecium development.

plant biology↗

bioRxiv2018

Cell-intrinsic Wnt4 controls early cDC1 commitment and suppresses development of pathogen-specific Type 2 immunity

Whether conventional dendritic cell (cDC) precursors acquire lineage-specific identity under direction of regenerative secreted glycoproteins within bone marrow niches is entirely unknown. Herein, we demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is both necessary and sufficient for necessary for the full extent of pre-cDC1 specification within bone marrow. Cell-intrinsic Wnt4 deficiency in CD11c+ cells reduced mature cDC1 numbers in BM, spleen, lung, and intestine and, reciprocally, rWnt4 treatment promoted pJNK activation and cDC1 expansion. Lack of cell-intrinsic Wnt4 in mice CD11cCreWnt4flox/flox impaired stabilization of IRF8/cJun complexes in BM and increased the basal frequency of both cDC2 and ILC2 populations in the periphery. Accordingly, CD11c-restricted Wnt4 augmented Type 2 immunity against the hookworm parasite Nippostrongylus brasiliensis accompanied by increased interleukin 5 production relative to CD11cCre controls. Collectively, these data show previously unappreciated role for Wnt4 in DC commitment and pathogen-specific immunity.

immunology↗

bioRxiv2018

LINGO3 interacts with Trefoil factor 2 to enforce mucosal barrier integrity and drive tissue repair during colitis

Mucosal epithelia are constantly exposed to damaging stimuli from mechanical, chemical, or biologic entities, and depend on rapid repair mechanisms to maintain tissue homeostasis and immunological quiescence. The reparative cytokine Trefoil factor 2 (TFF2) serves to enforce mucosal barrier integrity, but whether TFF2 receptor(s) exist is controversial. Herein, we demonstrate leucine rich repeat and immunoglobulin like domain containing nogo receptor interacting protein 3 (LINGO3) is a necessary transmembrane component for TFF2-mediated ERK signaling, proliferation, and recovery of trans-epithelial resistance of primary epithelia during wound healing. Human respiratory and intestinal epithelia express LINGO3 and mice lacking Lingo3 have impaired intestinal barrier function and fail to recover from DSS-induced colitis. Compared to wild-type controls, LINGO3 deficiency impairs both crypt regeneration and expression of the intestinal stem cell marker Lgr5. Importantly, Lingo3-/- mice display a phenotype similar to that previously reported for Tff2 deficiency, with increased paracellular permeability, and significant accumulation of mucosal CD4+ TH1 cells expressing IFN{gamma}+ TNF+ even under steady-state conditions. Combined, these data reveal a previously unrecognized role for LINGO3 as a putative TFF2 receptor that regulates mucosal barrier integrity and GI inflammation.\n\nSignificanceIntestinal epithelial cells (IEC) are necessary for maintenance of homeostasis, resistance to infectious organisms, and overall organismal health. When injured the IEC and the underlying stroma and progenitor cell pool undergo restitutive and regenerative processes driven by the reparative cytokine Trefoil factor 2 (TFF2). This report identifies a novel receptor component for TFF2 signaling expressed on both human and mouse epithelial cells that is necessary for barrier integrity at the steady state and during colitic disease. The discovery of a novel TFF2-LINGO3 axis sheds new light on the processes controlling tissue repair, restitution, and regeneration at the mucosal interface.

cell biology↗

bioRxiv2018

TFF3 is a ligand for LINGO2 that de-represses EGFR to control disease outcome during colitis and gastrointestinal nematode infection

Intestinal epithelial cells (IEC) comprise diverse lineages that serve distinct roles necessary for regulation of nutrient absorption, regeneration, immunity, and homeostasis1,2. Goblet cells secrete Trefoil factor 3 (TFF3) to maintain mucus viscosity and drive mucosal healing by inhibiting cell death and influencing tight junction protein expression3. However, whether TFF3 signaling relies upon conventional ligand-receptor interactions has been unclear for decades. This study demonstrates that the orphan transmembrane protein leucine rich repeat receptor and nogo-interacting protein 2 (LINGO2) immunoprecipitates with TFF3, that LINGO2 and TFF3 co-localize at the IEC cell surface, and that TFF3/LINGO2 interactions block IEC apoptosis. Loss of function studies show that TFF3-driven STAT3 and EGFR activation are both LINGO2 dependent. Importantly, we demonstrate that TFF3 disrupts LINGO2/EGFR interactions that normally restrict EGFR activity, resulting in enhanced EGFR signaling. Excessive EGFR activation in Lingo2 gene deficient mice exacerbates colitic disease and accelerates host resistance to parasitic nematodes, whereas TFF3 deficiency results in host susceptibility. Thus, our data demonstrating that TFF3 functions through a previously unrecognized ligand-receptor interaction with LINGO2 to de-repress LINGO2-dependent inhibition of EGFR activation provides a novel conceptual framework explaining how TFF3-mediates mucosal wound healing through enhanced activation of the EGFR pathway.

cell biology↗