Maria Rosaria Vitale

All Publications

• Novel Therapeutic Approach Targeting CXCR3 to Treat Immunotherapy Myocarditis. Circulation research Huang, Y. V., Sun, Y., Chou, H., Wagner, N., Vitale, M. R., Bayer, A. L., Xu, B., Lee, D., Lin, Z., Branche, C., Waliany, S., Neal, J. W., Wakelee, H. A., Witteles, R. M., Nguyen, P. K., Graves, E. E., Berry, G. J., Alcaide, P., Wu, S. M., Zhu, H. 2025

  Abstract

  Immune checkpoint inhibitors (ICIs) are successful in treating many cancers but may cause immune-related adverse events. ICI-mediated myocarditis has a high fatality rate with severe cardiovascular consequences. Targeted therapies for ICI myocarditis are currently limited.We used a genetic mouse model of PD1 deletion (MRL/Pdcd1-/-) along with a novel drug-treated ICI myocarditis mouse model to recapitulate the disease phenotype. We performed single-cell RNA-sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes on immune cells isolated from MRL and MRL/Pdcd1-/- mice at serial time points. We assessed the impact of macrophage deletion in MRL/Pdcd1-/- mice, then inhibited CXCR3 (C-X-C motif chemokine receptor 3) in ICI-treated mice to assess the therapeutic effect on myocarditis phenotype. Furthermore, we delineated the functional and mechanistic effects of CXCR3 blockade on T-cell and macrophage interactions. We then correlated the results in human single-cell multiomics data from blood and heart biopsy data from patients with ICI myocarditis.Single-cell multiomics demonstrated expansion of CXCL (C-X-C motif chemokine ligand) 9/10+CCR2+ macrophages and CXCR3hi (C-X-C motif chemokine receptor 3 high-expressing) CD8+ (cluster of differentiation) effector T lymphocytes in the hearts of MRL/Pdcd1-/- mice correlating with onset of myocarditis development. Both depletion of CXCL9/10+CCR2+ (C-C motif chemokine receptor) macrophages and CXCR3 blockade, respectively, led to decreased CXCR3hi CD8+ T-cell infiltration into the heart and significantly improved survival. Transwell migration assays demonstrated that the selective blockade of CXCR3 and its ligand, CXCL10, reduced CXCR3+CD8+ T-cell migration toward macrophages, implicating this interaction in T-cell cardiotropism toward cardiac macrophages. Furthermore, cardiomyocyte apoptosis was induced by CXCR3hi CD8+ T cells. Cardiac biopsies from patients with confirmed ICI myocarditis demonstrated infiltrating CXCR3+ T cells and CXCL9+/CXCL10+ macrophages. Both mouse cardiac immune cells and patient peripheral blood immune cells revealed expanded TCR s (T-cell receptors) correlating with CXCR3hi CD8+ T cells in ICI myocarditis samples.These findings bring forth the CXCR3-CXCL9/10 axis as an attractive therapeutic target for ICI myocarditis treatment, and more broadly as a druggable pathway in cardiac inflammation.

  View details for DOI 10.1161/CIRCRESAHA.124.325652

  View details for PubMedID 39931812

• Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks MOLECULAR PSYCHIATRY Mossink, B., Van Rhijn, J., Wang, S., Linda, K., Vitale, M. R., Zoller, J. M., van Hugte, E. H., Bak, J., Verboven, A. A., Selten, M., Negwer, M., Latour, B. L., van der Werf, I., Keller, J. M., Gunnewiek, T., Schoenmaker, C., Oudakker, A., Anania, A., Jansen, S., Lesch, K., Frega, M., van Bokhoven, H., Schubert, D., Kasri, N. 2022; 27 (1): 1-18

  Abstract

  Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.

  View details for DOI 10.1038/s41380-021-01117-x

  View details for Web of Science ID 000648813500001

  View details for PubMedID 33972691

  View details for PubMedCentralID PMC8960401