Biology subjects

Lacroix, S.

Publications and source records attributed to Lacroix, S..

5 recordsLinked to original sources

bioRxiv2026

Multimodal transcriptomics and calcium imaging reveal a novel subset of polymodal nociceptors expressing the interleukin 1 receptor in mice

We previously established that sensory neurons in the mouse dorsal root ganglia (DRG) express a functional receptor for the proinflammatory cytokine interleukin (IL)-1. We also demonstrated that deletion of the IL-1 receptor type 1 gene, Il1r1, in TRPV1-expressing (+) neurons prevented pain in models of chronic inflammatory diseases such as multiple sclerosis, rheumatoid arthritis and osteoarthritis. Here, we found a marked sex difference in the abundance of IL-1R1+ neurons, which represented approximately 10% of all DRG neurons in females but only 5% in males. However, male mice exhibited stronger, longer-lasting mechanical hypersensitivity than females after IL-1{beta} injection into the cerebrospinal fluid. In vivo calcium imaging revealed that IL-1{beta}- responsive DRG neurons responded to cutaneous mechanical and capsaicin stimulation. By integrating spatial transcriptomics with single-cell RNA sequencing (scRNA-Seq), we identified a gene signature uniquely marking IL-1R1+ neurons, including genes such as Ada, Cysltr2, Gpr139, Htr1a, Htr1f, Il31ra, Nppb, Npy2r, Nts, P2rx2, Pde4c, and Sst, with Ada and Sst validated at the protein level. Omics analysis revealed that IL-1R1+ DRG neurons form a subset of non-peptidergic type 3 (NP3) sensory neurons, which are linked to inflammatory pain and itch. However, Il1r1 deletion did not affect itch responses to serotonin, histamine, or chloroquine, and these mediators failed to induce calcium activity in IL-1{beta}-responsive DRG neurons. Finally, scRNA-seq identified several genes upregulated in NP3 neurons after IL-1{beta} injection, including Alkal2, Bdnf, and Lcn2, associated with chronic inflammatory pain. Thus, our study unveils novel markers for IL-1R1+ nociceptors and reaffirms their selective role in inflammatory pain.

neuroscience↗

bioRxiv2026

Immunoglobulins are rapidly internalized by neurons after CNS injury and cleared through lysosomal degradation

Spinal cord injury (SCI) causes hemorrhage and blood-spinal cord barrier disruption, allowing blood-derived molecules to infiltrate the parenchyma. While immunoglobulins (Ig) are abundant plasma proteins, their distribution and cellular targets within the injured spinal cord remain poorly defined. Here, we show that circulating non-autoimmune immunoglobulins rapidly infiltrate the spinal cord after injury in mice and disseminate beyond the lesion core. IgG, IgM, and IgA accumulate within the parenchyma early post-injury, with IgG displaying the widest spatial distribution, reaching distant spinal segments within hours. Neurons are the predominant cell type internalizing immunoglobulins in the gray matter, whereas astrocytes exhibit moderate uptake in white matter. Intra-cisterna magna administration of fluorescent serum-derived IgG reveals that neurons and astrocytes internalize IgG under physiological conditions, independently of Fc receptor engagement. Although the neonatal Fc receptor (FcRn) has minimal impact on CNS IgG recycling, its genetic deletion significantly improves locomotor recovery after SCI. Both in vitro and in vivo, neurons clear IgG through lysosomal degradation. Following SCI, inhibition of lysosomal proteases with the clinically approved drug E64d increases CNS IgG retention without compromising locomotor recovery. These findings establish neurons as key targets of circulating immunoglobulins after CNS injury and reveal IgG uptake and clearance pathways that may be leveraged to improve therapeutic performance of monoclonal antibody treatments.

neuroscience↗

bioRxiv2025

Parkinson's disease risk factors are expressed at brain barriers.

Parkinsons disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, but whether its etiology is cell autonomous remains unclear. Increasing evidence implicates the blood-central nervous system (CNS) barriers in disease development, highlighting the importance of identifying genetic risk factors linked to cells forming the cerebrovasculature to advance this emerging area of research. The objective of this study is to identify PD genetic risk factors associated with blood-brain (BBB) and blood-cerebrospinal fluid (BCSFB) barriers, and to validate protein localization in human tissue and experimental models. To do so, we integrated genome-wide association studies and single nuclei RNA-sequencing datasets from the human postmortem substantia nigra (SN), midbrain, or cortical samples from control and PD donors. An in-depth bioinformatics analysis identified genes enriched in cell types that form the multicellular architecture of brain barriers, including CAVIN2, ANXA1, ANO2, and LRP1B. We further validated whether corresponding proteins were present in cell types associated with the blood-CNS barriers in human and mouse post-mortem tissues, as well as in iPSC-differentiated cells and choroid plexus organoids. Results showed that quantifying the proportion of endothelial cells expressing PD-related genes was under-evaluated at the transcript level compared to immunofluorescence analyses. In addition, we observed that CAVIN2 and ANXA1 proteins were more abundant at the vasculature of the substantia nigra vs. cortex, and CAVIN2 protein levels were reduced in PD vs. control human postmortem tissues. In contrast, the investigation of mouse postmortem samples demonstrated that the CAVIN2 protein is only present in a subset of mouse blood vessels, compared to nearly all vessels in human tissue. Similarly, mouse ANXA1 protein localizes to dopaminergic neurons of the substantia nigra and not at the vasculature, as seen in human tissue. The primary outcome of this study is the identification of PD-relevant risk genes specifically expressed at brain barriers and enriched in PD-relevant brain regions. The secondary outcome is the demonstration of poor transcript-protein correlation in - at least - a subset of PD risk factors, and a low interspecies conservation of protein localization for the selected candidates. In conclusion, the BBB and BCSFB may represent understudied contributors to PD, endothelial-specific proteins appear differentially regulated compared to transcripts, and experimental models require comprehensive validation to ensure relevance to the human condition.

neuroscience↗

bioRxiv2019

MOG-reactive B cells exacerbate the severity of CD4+ T cell-driven CNS autoimmunity

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) that has traditionally been considered a T cell-mediated disease. However, accumulating evidence points to a crucial role for B cells in disease processes. IgH[MOG] mice possess a transgenic immunoglobulin heavy chain derived from a monoclonal antibody specific to myelin oligodendrocyte glycoprotein (MOG), a key target for autoimmune responses. Here, using the experimental autoimmune encephalomyelitis (EAE) model of MS, we investigated the susceptibility of IgH[MOG] mice to CD4+ T cell-driven disease that was induced by active immunization with MOG[35-55] autoantigen. We found that immunized IgH[MOG] mice rapidly developed severe EAE, characterized by the aggregation of T and B cells in the CNS meninges. We observed an increased presence of class-switched and inflammatory cytokine-positive B cells in the IgH[MOG] CNS, as well as a greater frequency of IL-17- and GM-CSF-producing CD4+ T cells. Production of the Th17 maintenance factor IL-23 was increased from IgH[MOG] CNS-infiltrating B cells, and in vivo blockade of IL-23p19 strongly attenuated disease severity in IgH[MOG] mice. Strikingly, we observed an increased frequency of PD-1+CXCR5- T peripheral helper (Tph)-like cells in the CNS parenchyma and dura mater of IgH[MOG] mice. Both Tph accumulation in the CNS, as well as meningeal inflammation, were again sharply reduced upon IL-23p19 blockade in vivo. Notably, CNS-infiltrating B and Tph cells from IgH[MOG] mice showed an upregulation of genes related to neurodegeneration and oxidative phosphorylation, and IL-23 blockade reduced ROS production from these cells in vivo. Altogether, these data show that MOG-specific B cells contribute to severe CD4+ T cell-driven EAE by promoting CNS accumulation of Th17 and Tph cells, as well as tertiary lymphoid organs in the CNS meninges, in an IL-23 dependent manner.

immunology↗

bioRxiv2018

Differential attenuation of β2 integrin-dependent and -independent neutrophil migration by Ly6G ligation

Abstract\n\nAntibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on {beta}2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin- independent neutrophil migration into inflamed lung. In peritoneum, the role of {beta}2 integrins varied with stimulus, proving dispensable for neutrophil entry in E. coli peritonitis but contributory in IL-1-mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin- mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of {beta}2 integrin dependence in neutrophil migration.\n\nKEY POINTSO_LIThe contribution of {beta}2 integrins to neutrophil migration into inflamed tissues varies with site and stimulus.\nC_LIO_LILigation of Ly6G, a GPI-linked neutrophil surface protein, selectively attenuates {beta}2 integrin-dependent neutrophil migration in vivo.\nC_LIO_LIBlockade correlates with disrupted interaction between Ly6G and {beta}2 integrins and impaired integrin-mediated postadhesion strengthening.\nC_LI

immunology↗