Biology subjects

Ciric, B.

Publications and source records attributed to Ciric, B..

6 recordsLinked to original sources

bioRxiv2026

Th17 effector cytokines induce shared and distinct microglial and endothelial cell responses in post-streptococcal encephalitis

Group A Streptococcus (GAS) infections can lead to neuropsychiatric sequelae in children, yet the mechanisms driving post-infectious brain pathology remain poorly defined. In a mouse disease model, Th17 lymphocytes induce microglial activation, blood-brain barrier (BBB) dysfunction, and neural circuit impairment; however, the transcriptional programs underlying these effects, and the specific Th17-derived cytokines involved are unclear. Using mouse genetics, single-cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory gene programs in microglia and brain endothelial cells (BECs), accompanied by downregulation of BBB-associated transcripts in BECs. Spatial transcriptomic analyses reveal that GAS-responsive microglia are enriched near infiltrating T cells. Several chemokines upregulated in microglia following GAS infection in mice are elevated in sera from affected patients. Conditional ablation of GM-CSF in CD4+ T cells partially attenuates microglial chemokine gene expression, but does not restore BBB integrity. Neutralization of IL-17A partially rescues BBB transcriptional changes in BECs and reduces microglial chemokine expression; however, compensatory peripheral immune responses associated with persistent infection exacerbate BBB disruption. In contrast, microglia/macrophage-specific deletion of IL-17 receptor A partially rescues BBB deficits following GAS infection. Together, these findings identify IL-17A-IL-17RA signaling in microglia as a critical driver of BBB dysfunction after GAS infections.

neuroscience↗

bioRxiv2025

Astrocyte-derived extracellular vesicles as antigen-specific therapy for neuromyelitis optica spectrum disorder in the mouse model

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by Th17 cell responses and serum antibodies against the water channel aquaporin-4 (AQP4) on astrocytes. To avoid systemic immunosuppression by current therapies, an approach is to induce antigen (Ag)-specific tolerance by injecting an AQP4 epitope used to trigger the disease (e.g., AQP4201-220). The prerequisite for Ag-specific therapy is identification of the target Ag; however, dozens of epitopes of AQP4 and certain non-AQP4 astrocyte Ags have been identified as auto-Ags in NMOSD patients and in animal models. This uncertainty regarding relevant astrocyte Ags would hinder the translation of this and similar experimental strategies into Ag-specific therapy for NMOSD patients. In our study, we developed a therapeutic approach for an experimental NMOSD (eNMOSD) mouse model that relies on astrocyte-derived extracellular vesicles (AST-EVs), which theoretically contain all astrocyte Ags. Intravenous injection of AST-EVs mitigates disease progression in an AQP-4 Ag-dependent manner in the eNMOSD model with ongoing disease. AST-EVs suppressed inflammation by decreasing immune cell infiltration of the CNS, inducing T cell apoptosis, and increasing the frequency of regulatory T cells and IL-35-producing B cells. Furthermore, we defined that IFN-{gamma} is crucial for successful i.v. tolerance induction by AST-EVs in eNMOSD. These novel findings represent a pioneering and considerable step toward a new therapeutic approach for NMOSD.

immunology↗

bioRxiv2025

GM-CSF production by immune cells in steady state and autoimmune neuroinflammation mapped using fate reporting mice

The full GM-CSF expression spectrum in immune cells remains unclear, while CD4{square} T cells are the primary source. Using novel GM-CSF reporter/fate reporter transgenic mice, we tracked ongoing and past (YFP+) GM-CSF expression in various immune cells. GM-CSF was produced by diverse immune cells, including CD4+, CD8+, {gamma}{delta} T, NK, B, and CD11b+ cells, with expression patterns varying by cell type and organ with liver CD4+ T cells and NK cells showing the highest expression history in both naive and mice with EAE. GM-CSF expression was transient and permanently lost in most cells over time. In a mouse model of multiple sclerosis, effector memory CD4{square} T cells were the dominant CNS GM-CSF source, with higher expression than in other organs. CD4+YFP+ T cells, strongly expressing CXCR6, produced multiple cytokines. Transcriptomic analysis showed distinct gene expression profiles in effector memory CD4+ T cells compared to naive cells. YFP{square} Tregs represent functionally distinct subsets mirroring effector Th cells, expressing cytokines associated with Th lineages, especially during neuroinflammation. These findings identified distinct GM-CSF cellular sources across organs, highlighting a transient tissue microenvironment influence on GM-CSF production linked to CXCR6 expression.

immunology↗

bioRxiv2025

CD11c+ CD8 T cells cause IFN-g-dependent autoimmune neuroinflammation that is restrained by PD-1 signaling.

In multiple sclerosis (MS) lesions, CD8 T cells outnumber CD4 T cells, suggesting that they contribute to MS pathology. However, little is known on the role of CD8 T cells in MS, partially due to the nearly ubiquitous use of experimental autoimmune encephalomyelitis (EAE) models that are mediated by CD4 T cells, with no CD8 T cell contribution. Importantly, MS and EAE differ in both their distribution of CNS lesions and their symptoms, indicating differences in CNS inflammation. MS lesions are more prevalent in the brain, while EAE lesions are more frequent in the spinal cord. Additionally, neurologic deficits in MS rarely parallel the paralysis typical for CD4 T cell-mediated EAE (CD4-EAE). In contrast, CD8-EAE models suggest that CD8 T cells preferentially cause brain inflammation, but little is known regarding how brain and spinal cord inflammation may differ, and how CD8 T cells may contribute to those differences. We have established an adoptive CD8-EAE mouse model characterized by brain-centered inflammation, severe ataxia, and weight loss. CNS inflammation in the brain and spinal cord differed in immune cell numbers, cellular composition, and inflammatory signatures. CD8-EAE could be suppressed by blocking IFN-{gamma}, and exacerbated by blocking PD-1, with concomitant changes in numbers of CNS-infiltrating monocytes. Most CD8 T cells in the CNS were CD11c+, suggesting that they are the pathogenic subset. We describe a robust CD8-EAE model, identify differences between brain and spinal cord inflammation, and characterize mechanisms that control CD8 T cell-mediated neuroinflammation, thereby furthering understanding of these cells in EAE/MS. Brief SummaryCD8 T cells are understudied in MS due to a lack of suitable animal models. We developed a CD8 T cell dependent model of MS.

immunology↗

bioRxiv2023

Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis

Group A Streptococcus (GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown. Using single-cell RNA sequencing and spatial transcriptomics, we found that ECs downregulate BBB genes and microglia upregulate interferon-response, chemokine and antigen-presentation genes after GAS infections. Several microglial-derived chemokines were elevated in patient sera. Administration of a neutralizing antibody against interleukin-17A (IL-17A), but not ablation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, partially rescued BBB dysfunction and microglial expression of chemokine genes. Thus, IL-17A is critical for neuropsychiatric sequelae of GAS infections and may be targeted to treat these disorders.

neuroscience↗

bioRxiv2020

Targeting CSF-1 ameliorates experimental autoimmune encephalomyelitis by depleting inflammatory monocytes and microglia in the central nervous system without affecting quiescent microglia.

The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is upregulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing mAb halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1, not IL-34. Both anti-CSF-1- and BLZ945-treatment greatly reduced numbers of monocyte-derived cells and microglia in the CNS. However, anti-CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti-CSF-1 treatments reduced the size of demyelinated lesions, and microglial activation in the grey matter. Lastly, we found that bone marrow-derived immune cells were the major mediators of CSF-1R-dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with total ablation of CSF-1R-dependent cells. Significance StatementMultiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases characterized by accumulation of myeloid immune cells into the central nervous system (CNS). Both harmful and beneficial myeloid cells are present in EAE/MS, and a goal of MS therapy is to preferentially remove harmful myeloid cells. The receptor for CSF-1 (CSF-1R) is found on myeloid cells and it is important for their survival. CSF-1R can bind two ligands, CSF-1 and IL-34, but is unknown whether their functions in EAE/MS differ. We found that blocking CSF-1 depleted only harmful myeloid cells in the CNS and suppressed EAE, whereas blocking IL-34 had no effect. Thus, we propose that blocking CSF-1 could be a novel therapy for MS.

immunology↗