About

Styliani-Anna E. Tsirka, PhD, is a SUNY Distinguished Professor and the Head of the Academy of Clinical and Educational Scholars at Stony Brook University. She holds a PhD in Biochemistry and a B.S. in Chemistry from Aristotle University of Thessaloniki, Greece. Her research focuses on neuro-immune interactions, specifically the communication, signaling events, and cell-cell interactions between cells in the central nervous system (CNS) parenchyma and microglia in both physiological and pathological conditions. Her work investigates the role of microglia, the immunocompetent cells of the CNS, in response to various stimuli and their involvement in diseases such as glioblastoma, stroke, multiple sclerosis, epilepsy, and major depression disorder. Dr. Tsirka's research aims to identify targets for intervention and therapeutic treatment of neurological and neuropsychiatric diseases. She has a significant background in studying inflammatory processes in the nervous system and has contributed to understanding neuro-immune pathways in health and disease.

Research topics

• Neuroscience
• Biology
• Endocrinology
• Cancer research
• Medicine
• Immunology
• Internal medicine

Selected publications

• Pde4 mediates MHCII expression in oligodendroglia

  Proceedings of the National Academy of Sciences · 2026-05-05

  articleOpen accessSenior author

  Chronic psychosocial stress is a major precipitant of Major Depressive Disorder (MDD), yet the glial mechanisms that translate sustained stress into maladaptive myelin and immune changes remain unclear. Using chronic social defeat stress and single-nucleus RNA sequencing of anterior medial PFC (mPFC) oligodendroglia, we identified a mature-oligodendrocyte cluster almost exclusively from stress-susceptible animals, marked by immune genes (MHCII) and upregulated Pde4b. Integration with a human MDD single-nucleus RNA sequencing dataset confirmed a conserved immune-like oligodendrocyte (ImOL) subset coexpressing Plp1 and Cd74 and enriched for Pde4b. Mechanistically, PDE4 inhibition with crisaborole elevated cAMP-PKA-CREB signaling, blocked IFNγ-induced MHCII expression, and engaged the eIF2α-ATF4/CHOP arm of the integrated stress response (ISR). In vivo modulation of the ISR with ISRIB or guanabenz bidirectionally controlled ImOL prevalence and stress-related behaviors. These findings position Pde4b-cAMP-ISR signaling as a regulator of oligodendroglial immune phenotypes and a promising target to modulate myelination and neuroinflammation in stress-related disorders.

  PublisherOA PDFDOI

• Abstract TP372: Establishing a Physiologically Variable Model of Ischemic Stroke to Recapitulate Patient Heterogeneity

  Stroke · 2025-01-30

  article

  Introduction: Ischemic stroke is highly heterogeneous, with patient-to-patient differences in infarct location, severity, and degree of reperfusion, among other factors. Incorporating this variability in preclinical stroke models is useful to more comprehensively recapitulate the patient population. Prior studies employ Longa (complete reperfusion) or Koizumi (chronic hyporeperfusion) murine models of stroke interchangeably over a range of ischemic durations. These models represent distinct stroke phenotypes, but the unique features of each model warrant further definition. Therefore, we sought to differentiate the pathology of these models to more accurately model patient heterogeneity. Methods: Transgenic mice expressing a fluorescent neutrophil marker (Ly6G-TdTomato) were subject to the Longa or Koizumi temporary middle cerebral artery occlusion (tMCAO) model of ischemic stroke. Ischemic duration was varied to model strokes of mild (30 min), moderate (60 min) and high (90 min) severity (n = 6-10 per experimental model). Laser speckle contrast imaging (LSCI) was performed at baseline, prior to and after reperfusion, and at endpoint to quantify cerebral blood flow (CBF) using a custom-made pixel assignment algorithm. Brains were collected at 24h or 72h and imaged via confocal microscopy to evaluate neutrophil infiltration in the ischemic hemisphere. Results: Mortality significantly increased with ischemic duration in the Koizumi model at 24h, 48h, and 72h, but did not differ across the Longa models. LSCI demonstrated a 2-to-5-fold increase in the area of profound ischemia (lowest quintile of pixel values) in the Koizumi model compared to the Longa model and with increasing ischemic duration. Additionally, the Koizumi model exhibited less restoration of CBF following reperfusion and more variability in CBF within the ischemic hemisphere regardless of ischemic duration. The number of infiltrating neutrophils increased 10-fold between the 30- and 90-min Longa and Koizumi models, but the Koizumi model demonstrated increased variability in the number of neutrophils at 24h and 72h. Conclusions: Our findings demonstrate differences in mortality, CBF, and immune response between stroke models of varying ischemic duration and reperfusion status. These unique pathological features can be linked to the physiological perturbations defining each model to establish a phenotypic spectrum that can be exploited to more thoroughly represent human stroke patient heterogeneity.

  PublisherDOI

• Targeting autophagy and plasminogen activator inhibitor-1 increases survival and remodels the tumor microenvironment in glioblastoma

  Journal of Experimental & Clinical Cancer Research · 2025-07-19 · 4 citations

  articleOpen accessSenior author

  BACKGROUND: Glioblastoma (GBM), the most common and aggressive type of primary brain tumor, engages multiple survival mechanisms, including autophagy. GBM exploits both degradative and secretory autophagy pathways to support tumor growth and limit the efficacy of standard-of-care treatments. We have previously shown that lucanthone, a blood-brain barrier permeable autophagy inhibitor, reduces tumor burden. However, although lucanthone-treated tumors are significantly smaller in size, they are not completely obliterated, suggesting compensatory survival mechanisms. A critical factor for GBM survival is communication with the tumor microenvironment (TME), which can be programmed by glioma cells to support growth and immunosuppression. Plasminogen activator inhibitor-1 (PAI-1), a secreted serine protease inhibitor, has been implicated in the progression of several cancers, including GBM, and has been shown to be modulated by autophagy in other cancers. The role of PAI-1 in GBM, namely its relationship with intracellular autophagy dysregulation and extracellular TME as a mechanism of tumor survival, remains incompletely understood. METHODS: Murine glioma models were established using intracranial injection of GL261 cells in C57BL/6 mice, followed by autophagy inhibition with intraperitoneal lucanthone and/or PAI-1 inhibition with MDI-2268 chow, and tumors were assessed by immunohistochemistry. In culture, glioma cell lines were challenged with MDI-2268, lucanthone, mitoxantrone, or siRNA-LNPs targeting PAI-1, and assessed by MTT assay, q-RT-PCR, ELISA, invasion assay, immunoblot, and immunocytochemistry. Lysosomal markers and transient transfection with fluorescent vesicular proteins were utilized to evaluate PAI-1 intracellular localization via confocal microscopy. Synergy was analyzed using the HSA model in Combenefit, and statistical analyses included t-tests, ANOVA, and log-rank tests for survival. RESULTS: Lucanthone treatment increased intracellular PAI-1 and autophagy markers while reducing active extracellular PAI-1. PAI-1 colocalized with lysosomal markers, suggesting impaired secretory autophagy. PAI-1 inhibition reduced glioma cell viability and invasion. Combination therapy with lucanthone and MDI-2268 drastically decreased tumor volume, prolonged survival, and promoted a pro-inflammatory state in the tumor microenvironment. CONCLUSIONS: Our findings suggest that PAI-1 may be a compensatory survival mechanism in GBM after autophagy inhibition, and that dual targeting of autophagy and PAI-1 disrupts tumor progression and enhances anti-tumor immunity, providing promising evidence for targeting this axis.

  PublisherDOI

• Editorial: Novel CNS targeting molecules, methods, and therapeutics in multiple sclerosis

  Frontiers in Immunology · 2025-09-18

  editorialOpen accessCorresponding

  Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease of the central nervous system (CNS), affecting nearly three million people worldwide. Understanding the progression of pathogenic alterations in the CNS during MS is critical for identifying therapeutic targets and improving diagnostic approaches. Novel drugs aimed at CNS pathology hold promise for enhancing treatment efficacy and reducing adverse effects. This Research Topic highlights recent advances in MS autoimmunity, with the goal of showcasing the development of targeted therapies and diagnostic strategies. Chen et al. investigated the relationship between microglial activation and remyelination status in MS. Microglia play a dual role: they facilitate clearance of myelin debris and promote the recruitment of oligodendrocyte precursor cells (OPCs) to lesion sites, but they also contribute to neuroinflammation, death of oligodendrocytes, and neuronal damage. The authors compared microglial subtypes and early-stage oligodendrocytes in remyelinated regions of MS patients, identifying differences between efficiently and poorly remyelinating individuals. Hoffrogge et al. reported that antagonism of the purinergic P2X7 receptor (P2X7R) ameliorates experimental autoimmune encephalomyelitis (EAE) by suppressing microglial activation without affecting the peripheral immune system. P2X7R, a ligand-gated ion channel activated by extracellular ATP, is strongly upregulated in reactive astrocytes and microglia within MS lesions. Sustained P2X7R activation contributes to lesion formation, suggesting that P2X7R antagonists hold therapeutic potential in MS. Sindi et al. demonstrated that positive allosteric modulators of AMPA-type glutamate receptors (AMPA-PAMs) protect against demyelination in the EAE and cuprizone models. AMPA-PAMs enhance synaptic transmission without causing excitotoxicity and exhibit neuroprotective effects. Notably, they increase OPC numbers, suggesting their potential in promoting remyelination. Neurpokoeva et al. proposed a novel diagnostic method for MS using blood serum surface-enhanced Raman scattering (SERS) combined with machine learning analysis. Compared to MRI, the current gold standard for detecting CNS demyelination, but with practical limitations, SERS offers exceptionally high specificity and sensitivity for diagnosing MS patients. Anandan et al. reviewed the potential of brain-derived blood biomarkers in MS. The authors provide a comprehensive summary of all biomarkers of the past, present, and future, including brain-derived extracellular vesicles, which may serve as valuable tools for diagnosis, prognosis, monitoring, and personalized treatment. Altogether, this Research Topic advances our understanding of CNS-targeted therapies and diagnostic innovations in MS, helping to shape future research agendas toward improving patient care.

  PublisherOA PDFDOI

• Abstract WP395: Mapping the Spatial Distribution of Neutrophils in a Murine Model of Ischemia/Reperfusion Injury

  Stroke · 2025-01-30

  article

  Introduction: Polymorphonuclear Neutrophils (PMNs) are the first blood-derived immune cells to respond in ischemia/reperfusion injury (I/RI). PMNs exhibit spatial heterogeneity and play complex roles in injury progression and resolution. However, preclinical studies investigating the immune response have been limited to studying the area of maximal infarction or highly representative images throughout the stroke hemisphere. As a result, the spatial relationships of PMNs in the acute stages of I/RI throughout the whole brain remain largely unknown. To address this gap in knowledge, we applied light sheet microscopy (LSM) to fully map the spatial patterns of PMNs in relation to neuronal injury throughout the murine brain in I/RI. Methods: The transient middle cerebral artery occlusion (tMCAO) model was used to recapitulate I/RI in a Ly6G-tdTomato transgenic mouse line expressing an endogenous fluorescent marker for PMNs. Mice were subject to 60 min or 90 min of ischemia to model strokes of varying severity. Whole brains were collected 72h post-tMCAO, (the point of maximal PMN infiltration), cleared, and then imaged using LSM. Brains were co-labeled with NeuN (neurons), registered, and parcellated according to the Allen Brain Atlas. Relationships of PMNs to the M1 segment of the MCA were then mapped. Results: Following 60 min tMCAO, PMNs infiltrated predominantly in infarcted regions of the cerebral cortex (NeuN Negative). Further, the density of PMNs was higher in anatomic regions supplied by the middle cerebral artery (MCA) and negatively correlated with the distance from the M1. In the 90 min tMCAO, PMN infiltration followed a similar pattern with PMN accumulation predominantly in the ischemic cortex and increased with proximity to the M1. However, PMN densities in the 90 min tMCAO were significantly higher than in the 60 min tMCAO. Additionally, PMN-rich regions in the 90 min tMCAO were more concentrated than in the 60 min tMCAO. Conclusions: Our data demonstrate that PMNs exhibit spatial heterogeneity following experimental stroke and cluster in regions corresponding to increased neuronal death and proximity to the MCA. PMN distribution was also influenced by the duration of ischemia, suggesting that PMNs are highly responsive to both stroke topology and severity. These data enable a more in-depth understanding of neutrophil dynamics in I/RI that can be leveraged to inform future stroke therapies directed at limiting the immune response.

  PublisherDOI

• Cover Image, Volume 73, Issue 6

  Glia · 2025-04-21

  paratextOpen accessSenior author
  PublisherOA PDFDOI

• Probing the optical properties and toxicological profile of zinc tungstate nanorods

  The Journal of Chemical Physics · 2024-06-17 · 2 citations

  articleOpen access

  Zinc tungstate is a semiconductor known for its favorable photocatalytic, photoluminescence, and scintillation properties, coupled with its relatively low cost, reduced toxicity, and high stability in biological and catalytic environments. In particular, zinc tungstate evinces scintillation properties, namely the ability to emit visible light upon absorption of energetic radiation such as x rays, which has led to applications not only as radiation detectors but also for biomedical applications involving the delivery of optical light to deep tissue, such as photodynamic therapy and optogenetics. Here, we report on the synthesis of zinc tungstate nanorods generated via an optimized but facile method, which allows for synthetic control over the aspect ratio of the as-synthesized anisotropic motifs via rational variation of the solution pH. We investigate the effect of aspect ratio on their resulting photoluminescent and radioluminescent properties. We further demonstrate the potential of these zinc tungstate nanorods for biomedical applications, such as photodynamic therapy for cancer treatment, by analyzing their toxicological profile within cell lines and neurons.

  PublisherOA PDFDOI

• Dementia after Ischemic Stroke, from Molecular Biomarkers to Therapeutic Options

  International Journal of Molecular Sciences · 2024-07-16 · 11 citations

  reviewOpen access

  Ischemic stroke is a leading cause of disability worldwide. While much of post-stroke recovery is focused on physical rehabilitation, post-stroke dementia (PSD) is also a significant contributor to poor functional outcomes. Predictive tools to identify stroke survivors at risk for the development of PSD are limited to brief screening cognitive tests. Emerging biochemical, genetic, and neuroimaging biomarkers are being investigated in an effort to unveil better indicators of PSD. Additionally, acetylcholinesterase inhibitors, NMDA receptor antagonists, dopamine receptor agonists, antidepressants, and cognitive rehabilitation are current therapeutic options for PSD. Focusing on the chronic sequelae of stroke that impair neuroplasticity highlights the need for continued investigative trials to better assess functional outcomes in treatments targeted for PSD.

  PublisherDOI

• Convergence of endothelial dysfunction, inflammation and glucocorticoid resistance in depression-related cardiovascular diseases

  BMC Immunology · 2024-09-27 · 22 citations

  reviewOpen accessSenior author

  Major Depressive Disorder, or depression, has been extensively linked to dysregulated HPA axis function, chronic inflammation and cardiovascular diseases. While the former two have been studied in depth, the mechanistic connection between depression and cardiovascular disease is unclear. As major mediators of vascular homeostasis, vascular pathology and immune activity, endothelial cells represent an important player connecting the diseases. Exaggerated inflammation and glucocorticoid function are important topics to explore in the endothelial response to MDD. Glucocorticoid resistance in several cell types strongly promotes inflammatory signaling and results in worsened severity in many diseases. However, endothelial health and inflammation in chronic stress and depression are rarely considered from the perspective of glucocorticoid signaling and resistance. In this review, we aim to discuss (1) endothelial dysfunction in depression, (2) inflammation in depression, (3) general glucocorticoid resistance in depression and (4) endothelial glucocorticoid resistance in depression co-morbid inflammatory diseases. We will first describe vascular pathology, inflammation and glucocorticoid resistance separately in depression and then describe their potential interactions with one another in depression-relevant diseases. Lastly, we will hypothesize potential mechanisms by which glucocorticoid resistance in endothelial cells may contribute to vascular disease states in depressed people. Overall, endothelial-glucocorticoid signaling may play an important role in connecting depression and vascular pathology and warrants further study.

  PublisherOA PDFDOI

• Oligodendroglia Are Primed for Antigen Presentation in Response to Chronic Stress‐Induced Microglial‐Derived Inflammation

  Glia · 2024-12-24 · 3 citations

  articleSenior authorCorresponding

  Chronic stress is a major contributor to the development of major depressive disorder, one of the leading causes of disability worldwide. Using a model of repeated social defeat stress in mice, we and others have reported that neuroinflammation plays a dynamic role in the development of behavioral deficits consistent with social avoidance and impaired reward responses. Animals susceptible to the model also exhibit hypomyelination in the medial prefrontal cortex, indicative of changes in the differentiation pathway of cells of the oligodendroglial lineage (OLN). We computationally confirmed the presence of immune oligodendrocytes, a population of OLN cells, which express immune markers and myelination deficits. In the current study, we report that microglia are necessary to induce expression of antigen presentation markers (and other immune markers) on oligodendroglia. We further associate the appearance of these markers with changes in the OLN and confirm that microglial changes precede OLN changes. Using co-cultures of microglia and OLN, we show that under inflammatory conditions the processes of phagocytosis and expression of MHCII are linked, suggesting potential priming for antigen presentation by OLN cells. Our findings provide insights into the nature of these OLN cells with immune capabilities, their obligatory interaction with microglia, and identify them as a potential cellular contributor to the pathological manifestations of psychosocial stress.

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Recent grants

• Training Program in Pharmacological Sciences

  NIH · $7.1M · 1977–2022

• NIH Grant R01NS042168

  NIH · $3.1M · 2013

• NIH Grant R29NS035843

  NIH · $100k · 1998

• Scholars in BioMedical Sciences (SBMS) Training Program

  NIH · $689k · 2018–2023

• NIH Grant R01NS035843

  NIH · $660k · 2002

Frequent coauthors

• Miguel M. Madeira

  39 shared

• Jeremy Tetsuo Miyauchi

  36 shared

• Daniel P. Radin

  26 shared

• Michael D. Caponegro

  24 shared

• Stephen L. Dewey

  22 shared

• Jillian C. Nissen

  SUNY Old Westbury

  21 shared

• Danling Chen

  19 shared

• Zachary Hage

  Stony Brook School

  19 shared

Labs

• Styliani-Anna E. Tsirka LabPI

Education

• PhD, Biochemistry

  Aristotle University of Thessaloniki

  1989

• BS, Chemistry

  Aristotle University of Thessaloniki

  1984

Awards & honors

• SUNY Chancellor’s Award for Excellence in University Service
• Mentor of Excellence Award from the SBU Center for Inclusive…
• Fellow of the American Association for the Advancement of Sc…