Stem cell grafts enhance endogenous extracellular vesicle expression in the stroke brain.

Endogenous brain repair occurs following an ischemic stroke but is transient, thus unable to fully mount a neuroprotective response against the evolving secondary cell death. Finding a treatment strategy that may render robust and long-lasting therapeutic effects stands as a clinically relevant therapy for stroke. Extracellular vesicles appear to be upregulated after stroke, which may represent a candidate target for neuroprotection. In this study, we probed whether transplanted stem cells could enhance the expression of extracellular vesicles to afford stable tissue remodeling in the ischemic stroke brain. Aged rats were initially exposed to the established ischemic stroke model of middle cerebral artery occlusion then received intravenous delivery of either bone marrow-derived mesenchymal stem cell transplantation or vehicle. A year later, the animals were assayed for brain damage, inflammation, and extracellular vesicle expression. Our findings revealed that while core infarction was not reduced, the stroke animals transplanted with stem cells displayed a significant reduction in peri-infarct cell loss that coincided with downregulated Iba1-labeled inflammatory cells and upregulated CD63-positive extracellular vesicles that appeared to be co-localized with GFAP-positive astrocytes. Interestingly, grafted stem cells were not detected at one year post-transplantation period, suggesting that the extracellular vesicles likely originated within the host brain. That long-lasting functional benefits persisted in the absence of surviving transplanted stem cells, but with upregulation of endogenous extracellular vesicles, advances the concept that transplantation of stem cells acutely after stroke propels host extracellular vesicles to the ischemic brain, altogether promoting chronic brain remodeling.

Cytokine-armed oncolytic herpes simplex viruses: a game-changer in cancer immunotherapy?

Cytokines are small proteins that regulate the growth and functional activity of immune cells, and several have been approved for cancer therapy. Oncolytic viruses are agents that mediate antitumor activity by directly killing tumor cells and inducing immune responses. Talimogene laherparepvec is an oncolytic herpes simplex virus type 1 (oHSV), approved for the treatment of recurrent melanoma, and the virus encodes the human cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). A significant advantage of oncolytic viruses is the ability to deliver therapeutic payloads to the tumor site that can help drive antitumor immunity. While cytokines are especially interesting as payloads, the optimal cytokine(s) used in oncolytic viruses remains controversial. In this review, we highlight preliminary data with several cytokines and chemokines, including GM-CSF, interleukin 12, FMS-like tyrosine kinase 3 ligand, tumor necrosis factor α, interleukin 2, interleukin 15, interleukin 18, chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 4, or their combinations, and show how these payloads can further enhance the antitumor immunity of oHSV. A better understanding of cytokine delivery by oHSV can help improve clinical benefit from oncolytic virus immunotherapy in patients with cancer.

Tumor Microenvironment: A Niche for Cancer Stem Cell Immunotherapy.

Tumorigenic Cancer Stem Cells (CSCs), often called tumor-initiating cells (TICs), represent a unique subset of cells within the tumor milieu. They stand apart from the bulk of tumor cells due to their exceptional self-renewal, metastatic, and differentiation capabilities. Despite significant progress in classifying CSCs, these cells remain notably resilient to conventional radiotherapy and chemotherapy, contributing to cancer recurrence. In this review, our objective is to explore novel avenues of research that delve into the distinctive characteristics of CSCs within their surrounding tumor microenvironment (TME). We will start with an overview of the defining features of CSCs and then delve into their intricate interactions with cells from the lymphoid lineage, namely T cells, B cells, and natural killer (NK) cells. Furthermore, we will discuss their dynamic interplay with myeloid lineage cells, including macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). Moreover, we will illuminate the crosstalk between CSCs and cells of mesenchymal origin, specifically fibroblasts, adipocytes, and endothelial cells. Subsequently, we will underscore the pivotal role of CSCs within the context of the tumor-associated extracellular matrix (ECM). Finally, we will highlight pre-clinical and clinical studies that target CSCs within the intricate landscape of the TME, including CAR-T therapy, oncolytic viruses, and CSC-vaccines, with the ultimate goal of uncovering novel avenues for CSC-based cancer immunotherapy.

Viral Vectors Expressing Interleukin 2 for Cancer Immunotherapy.

Interleukin 2 (IL-2) plays a crucial role in T cell growth and survival, enhancing the cytotoxic activity of natural killer and cytotoxic T cells and thus functioning as a versatile master proinflammatory anticancer cytokine. The FDA has approved IL-2 cytokine therapy for the treatment of metastatic melanoma and metastatic renal cell carcinoma. However, IL-2 therapy has significant constraints, including a short serum half-life, low tumor accumulation, and life-threatening toxicities associated with high doses. Oncolytic viruses (OVs) offer a promising option for cancer immunotherapy, selectively targeting and destroying cancer cells while sparing healthy cells. Numerous studies have demonstrated the successful delivery of IL-2 to the tumor microenvironment without compromising safety using OVs such as vaccinia, Sendai, parvo, Newcastle disease, tanapox, and adenoviruses. Additionally, by engineering OVs to coexpress IL-2 with other anticancer transgenes, the immune properties of IL-2 can be further enhanced. Preclinical and clinical studies have shown promising antitumor effects of IL-2-expressing viral vectors, either alone or in combination with other anticancer therapies. This review summarizes the therapeutic potential of IL-2-expressing viral vectors and their antitumor mechanisms of action.

Profiling and targeting cancer stem cell signaling pathways for cancer therapeutics.

Tumorigenic cancer stem cells (CSCs) represent a subpopulation of cells within the tumor that express genetic and phenotypic profiles and signaling pathways distinct from the other tumor cells. CSCs have eluded many conventional anti-oncogenic treatments, resulting in metastases and relapses of cancers. Effectively targeting CSCs' unique self-renewal and differentiation properties would be a breakthrough in cancer therapy. A better characterization of the CSCs' unique signaling mechanisms will improve our understanding of the pathology and treatment of cancer. In this paper, we will discuss CSC origin, followed by an in-depth review of CSC-associated signaling pathways. Particular emphasis is given on CSC signaling pathways' ligand-receptor engagement, upstream and downstream mechanisms, and associated genes, and molecules. Signaling pathways associated with regulation of CSC development stand as potential targets of CSC therapy, which include Wnt, TGFß (transforming growth factor-ß)/SMAD, Notch, JAK-STAT (Janus kinase-signal transducers and activators of transcription), Hedgehog (Hh), and vascular endothelial growth factor (VEGF). Lastly, we will also discuss milestone discoveries in CSC-based therapies, including pre-clinical and clinical studies featuring novel CSC signaling pathway cancer therapeutics. This review aims at generating innovative views on CSCs toward a better understanding of cancer pathology and treatment.

Combined space stressors induce independent behavioral deficits predicted by early peripheral blood monocytes.

Interplanetary space travel poses many hazards to the human body. To protect astronaut health and performance on critical missions, there is first a need to understand the effects of deep space hazards, including ionizing radiation, confinement, and altered gravity. Previous studies of rodents exposed to a single such stressor document significant deficits, but our study is the first to investigate possible cumulative and synergistic impacts of simultaneous ionizing radiation, confinement, and altered gravity on behavior and cognition. Our cohort was divided between 6-month-old female and male mice in group, social isolation, or hindlimb unloading housing, exposed to 0 or 50 cGy of 5 ion simplified simulated galactic cosmic radiation (GCRsim). We report interactions and independent effects of GCRsim exposure and housing conditions on behavioral and cognitive performance. Exposure to GCRsim drove changes in immune cell populations in peripheral blood collected early after irradiation, while housing conditions drove changes in blood collected at a later point. Female mice were largely resilient to deficits observed in male mice. Finally, we used principal component analysis to represent total deficits as principal component scores, which were predicted by general linear models using GCR exposure, housing condition, and early blood biomarkers.

Stem Cell Therapy for Sequestration of Traumatic Brain Injury-Induced Inflammation.

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn into a "reactive" state, characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Other injuries to the brain, including radiation exposure, may trigger TBI-like pathology, characterized by inflammation. Currently there are no treatments to prevent or reverse the deleterious consequences of brain trauma. The recognition that TBI predisposes stem cell alterations suggests that stem cell-based therapies stand as a potential treatment for TBI. Here, we discuss the inflamed brain after TBI and radiation injury. We further review the status of stem cells in the inflamed brain and the applications of cell therapy in sequestering inflammation in TBI.

Stem Cells for Aging-Related Disorders.

This review captures recent advances in biological and translational research on stem cells. In particular, we discuss new discoveries and concepts regarding stem cell treatment of aging-related disorders. A myriad of stem cell sources exists, from hematopoietic to mesenchymal and neural cell lineages. We examine current applications of exogenous adult bone marrow-derived stem cells as an effective and safe transplantable cell source, as well as the use of electrical stimulation to promote endogenous neurogenesis for Parkinson's disease. We also explore the potential of transplanting exogenous umbilical cord blood cells and mobilizing host resident stem cells in vascular dementia and aging. In addition, we assess the ability of small molecules to recruit resident stem cells in Alzheimer's disease. Finally, we evaluate mechanisms of action recently implicated in stem cell therapy, such as the role of long non-coding RNAs, G-protein coupled receptor 5, and NeuroD1. Our goal is to provide a synopsis of recent milestones regarding the application of stem cells in aging.

IL-2/IL-2R Antibody Complex Enhances Treg-Induced Neuroprotection by Dampening TNF-α Inflammation in an In Vitro Stroke Model.

The present in vitro study showed that IL-2/IL-2R antibody complex facilitates Treg-induced neuroprotection in the oxygen glucose deprivation/reoxygenation (OGD/R) model of stroke. First, we examined the role of IL-2/IL-2R-treated Tregs in OGD/R-exposed rat primary cortical cells (PCCs), which represent the cell type of the ischemic gray matter in the stroke brain. Here, OGD/R induced cell death, which was attenuated by Tregs and more robustly by IL-2/IL-2R-treated Tregs, but not by IL-2/IL-2R treatment alone. Second, we next assessed IL-2/IL-2R effects in OGD/R-exposed human oligodendrocyte progenitor cells (OPCs), which correspond to the white matter injury after stroke. Results revealed that a similar pattern neuroprotection as seen in the gray matter, in that OGD/R triggered cell death, which was ameliorated by Tregs and more effectively by IL-2/IL-2R-treated Tregs, but IL-2/IL-2R treatment alone was not therapeutic. Third, as we begin to understand the mechanism underlying IL-2/IL-2R engagement of Tregs, we investigated the inflammatory response in OGD/R-exposed human neural progenitor cells (NPCs), which recapitulate both ischemic gray and white matter damage in stroke. Similar to PCCs and OPCs, OGD/R produced cell death and was blocked by Tregs and more efficiently by IL-2/IL-2R-treated Tregs, whereas IL-2/IL-2R treatment alone did not alter the ischemic insult. Moreover, the inflammatory marker, TNF-α, was upregulated after OGD/R, dampened by both Tregs and more efficiently by IL-2/IL-2R-treated Tregs but more pronounced in the latter, and not affected by IL-2/IL-2R treatment alone, suggesting IL-2/IL-2R-Treg-mediated modulation of inflammatory response in stroke. Altogether, these observations support the use of IL-2/IL-2R treatment in enhancing the anti-inflammatory effects of Tregs in stroke.

Biphasic roles of pentraxin 3 in cerebrovascular function after white matter stroke.

Recent clinical studies suggest that pentraxin 3 (PTX3), which is known as an acute-phase protein that is produced rapidly at local sites of inflammation, may be a new biomarker of disease risk for central nervous system disorders, including stroke. However, the effects of PTX3 on cerebrovascular function in the neurovascular unit (NVU) after stroke are mostly unknown, and the basic research regarding the roles of PTX3 in NVU function is still limited. In this reverse translational study, we prepared mouse models of white matter stroke by vasoconstrictor (ET-1 or L-Nio) injection into the corpus callosum region to examine the roles of PTX3 in the pathology of cerebral white matter stroke. PTX3 expression was upregulated in GFAP-positive astrocytes around the affected region in white matter for at least 21 days after vasoconstrictor injection. When PTX3 expression was reduced by PTX3 siRNA, blood-brain barrier (BBB) damage at day 3 after white matter stroke was exacerbated. In contrast, when PTX3 siRNA was administered at day 7 after white matter stroke, compensatory angiogenesis at day 21 was promoted. In vitro cell culture experiments confirmed the inhibitory effect of PTX3 in angiogenesis, that is, recombinant PTX3 suppressed the tube formation of cultured endothelial cells in a Matrigel-based in vitro angiogenesis assay. Taken together, our findings may support a novel concept that astrocyte-derived PTX3 plays biphasic roles in cerebrovascular function after white matter stroke; additionally, it may also provide a proof-of-concept that PTX3 could be a therapeutic target for white matter-related diseases, including stroke.

Fighting the War Against COVID-19 via Cell-Based Regenerative Medicine: Lessons Learned from 1918 Spanish Flu and Other Previous Pandemics.

The human population is in the midst of battling a rapidly-spreading virus- Severe Acute Respiratory Syndrome Coronavirus 2, responsible for Coronavirus disease 2019 or COVID-19. Despite the resurgences in positive cases after reopening businesses in May, the country is seeing a shift in mindset surrounding the pandemic as people have been eagerly trickling out from federally-mandated quarantine into restaurants, bars, and gyms across America. History can teach us about the past, and today's pandemic is no exception. Without a vaccine available, three lessons from the 1918 Spanish flu pandemic may arm us in our fight against COVID-19. First, those who survived the first wave developed immunity to the second wave, highlighting the potential of passive immunity-based treatments like convalescent plasma and cell-based therapy. Second, the long-term consequences of COVID-19 are unknown. Slow-progressive cases of the Spanish flu have been linked to bacterial pneumonia and neurological disorders later in life, emphasizing the need to reduce COVID-19 transmission. Third, the Spanish flu killed approximately 17 to 50 million people, and the lack of human response, overcrowding, and poor hygiene were key in promoting the spread and high mortality. Human behavior is the most important strategy for preventing the virus spread and we must adhere to proper precautions. This review will cover our current understanding of the pathology and treatment for COVID-19 and highlight similarities between past pandemics. By revisiting history, we hope to emphasize the importance of human behavior and innovative therapies as we wait for the development of a vaccine. Graphical Abstract.

The Disillusioned Comfort with COVID-19 and the Potential of Convalescent Plasma and Cell Therapy.

Coronavirus disease 2019 or COVID-19 is highly infectious, which can lead to acute and chronic debilitating symptoms, as well as mortality. The advent of safe and effective vaccines or antiviral drugs remains distant in the future. Practical public health measures, such as social distancing, hand washing, and wearing a face mask, are the current recommended guidelines by the Centers for Disease Control and Prevention for limiting the spread of the virus. Weakened immune system and aberrant inflammation represent a major pathological symptom of COVID-19 patients. Based on the unique immunomodulatory properties of both convalescent plasma and stem cells, we discuss here their potential use for treating COVID-19.

Brief overview: Protective roles of astrocyte-derived pentraxin-3 in blood-brain barrier integrity.

Stroke is one of the world's leading causes of mortality and morbidity. Greater understanding is required of the underlying relationships in ischemic brains in order to prevent stroke or to develop effective treatment. This review highlights new findings about the relationship of blood-brain barrier with astrocytes, pentraxin-3 (PTX3), and other factors expressed during or after ischemic stroke. These are discussed with respect to their ameliorative or deleterious effects. These effects are measured in vivo in animal models as well as in vitro in cell cultures. Evidence was found to suggest that astrocytes play a key role in stroke by expressing PTX3, which, in turn, enhances endothelial tightness, increases tight junction proteins, and inhibits vascular endothelial growth factor. The role of astrocytes and PTX3 is examined in relation to hypoxic stress and conditioning as well as mitochondrial transfer. Astrocytes and PTX3 are placed in the context of brain circulation and related areas.

Astrocyte-Derived Pentraxin 3 Supports Blood-Brain Barrier Integrity Under Acute Phase of Stroke.

BACKGROUND AND PURPOSE: Pentraxin 3 (PTX3) is released on inflammatory responses in many organs. However, roles of PTX3 in brain are still mostly unknown. Here we asked whether and how PTX3 contributes to blood-brain barrier dysfunction during the acute phase of ischemic stroke. METHODS: In vivo, spontaneously hypertensive rats were subjected to focal cerebral ischemia by transient middle cerebral artery occlusion. At day 3, brains were analyzed to evaluate the cellular origin of PTX3 expression. Correlations with blood-brain barrier breakdown were assessed by IgG staining. In vitro, rat primary astrocytes and rat brain endothelial RBE.4 cells were cultured to study the role of astrocyte-derived PTX3 on vascular endothelial growth factor-mediated endothelial permeability. RESULTS: During the acute phase of stroke, reactive astrocytes in the peri-infarct area expressed PTX3. There was negative correlation between gradients of IgG leakage and PTX3-positive astrocytes. Cell culture experiments showed that astrocyte-conditioned media increased levels of tight junction proteins and reduced endothelial permeability under normal conditions. Removing PTX3 from astrocyte-conditioned media by immunoprecipitation increased endothelial permeability. PTX3 strongly bound vascular endothelial growth factor in vitro and was able to decrease vascular endothelial growth factor-induced endothelial permeability. CONCLUSIONS: Astrocytes in peri-infarct areas upregulate PTX3, which may support blood-brain barrier integrity by regulating vascular endothelial growth factor-related mechanisms. This response in astrocytes may comprise a compensatory mechanism for maintaining blood-brain barrier function after ischemic stroke.

Acupuncture-Induced Analgesia: The Role of Microglial Inhibition.

The last three decades have documented preclinical and clinical data supporting the use of acupuncture in relieving symptoms of many diseases, including allergies, infections, and neurological disorders. The advent of electroacupuncture has not only modernized the practice of acupuncture, but also has improved its efficacy, especially for producing analgesic-like effects. Although the mechanism of action of acupuncture-induced analgesia remains largely unknown, several lines of investigation have implicated modulation of pain processes via brain opioid signaling and neuroimmunoregulatory pathways. Here, we review key findings demonstrating the efficacy and underlying mechanisms of acupuncture-induced analgesia. In particular, we discuss potent analgesic effects of acupuncture via neural pain processes through inhibition of microglial activation. The safe and effective use of acupuncture stands as a nonpharmacological alternative for induction of analgesia, which has direct clinical applications, especially for pain-related diseases.

Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells.

Mesenchymal stromal cells (MSCs) are multi-potent cells that have the capability of differentiating into adipogenic, osteogenic, chondrogenic and neural cells. With these multiple capabilities, MSCs have been highly regarded as an effective transplantable cell source for regenerative medicine. A large bank of these cells can be found in several regions of the human umbilical cord, including the umbilical cord lining, the subendothelial layer, the perivascular zone and, most important, in Wharton jelly (WJ). These cells, all umbilical cord-derived MSCs, are durable, have large loading capacities and are considered ethical to harvest because the umbilical cord is often considered waste. These logistical advantages make WJ as appealing source of stem cells for transplant therapy. In particular, WJ is a predominantly good source of cells because MSCs in WJ are maintained in an early embryologic phase and therefore have retained some of the primitive stemness properties. WJ-MSCs can easily differentiate into a plethora of cell types leading to a variety of applications. In addition, WJ-MSCs are slightly easier to harvest compared with other MSCs (such as bone marrow-derived MSCs). The fascinating stemness properties and therapeutic potential of WJ-MSCs provide great promise in many aspects of regenerative medicine and should be considered for further investigations as safe and effective donor cells for transplantation therapy in many debilitating disorders, which are discussed here. We previously reviewed the therapeutic potential of WJ-MSCs and now provide an update on their recent preclinical and clinical applications.

Adult stem cell transplantation: is gender a factor in stemness?

Cell therapy now constitutes an important area of regenerative medicine. The aging of the population has mandated the discovery and development of new and innovative therapeutic modalities to combat devastating disorders such as stroke. Menstrual blood and Sertoli cells represent two sources of viable transplantable cells that are gender-specific, both of which appear to have potential as donor cells for transplantation in stroke. During the subacute phase of stroke, the use of autologous cells offers effective and practical clinical application and is suggestive of the many benefits of using the aforementioned gender-specific cells. For example, in addition to being exceptionally immunosuppressive, testis-derived Sertoli cells secrete many growth and trophic factors and have been shown to aid in the functional recovery of animals transplanted with fetal dopaminergic cells. Correspondingly, menstrual blood cells are easily obtainable and exhibit angiogenic characteristics, proliferative capability, and pluripotency. Of further interest is the ability of menstrual blood cells, following transplantation in stroke models, to migrate to the infarct site, secrete neurotrophic factors, regulate the inflammatory response, and be steered towards neural differentiation. From cell isolation to transplantation, we emphasize in this review paper the practicality and relevance of the experimental and clinical use of gender-specific stem cells, such as Sertoli cells and menstrual blood cells, in the treatment of stroke.

Suppressed cytokine expression immediatey following traumatic brain injury in neonatal rats indicates an expeditious endogenous anti-inflammatory response.

The timing of therapeutic intervention in traumatic brain injury (TBI) is critical. Although immediate cell death cascades have become established in adult TBI, the pathophysiology underlying neonatal TBI is poorly understood. The objective of the present study was to determine the role of cytokine regulation following TBI in neonatal rats. Seven-day-old Sprague-Dawley rats were subjected to TBI using the controlled cortical impact (CCI) injury model. Age-matched littermates that did not receive TBI served as the controls. Immediately following TBI, rats were euthanized, and the brains were divided into the ipsilateral and contralateral hemispheres then flash frozen. A BioRad 23-Plex panel was used to measure cytokine levels. Surprisingly, the data revealed that 18 of the 23 cytokines analyzed were significantly downregulated in the hemisphere contralateral to the TBI impacted hemisphere. IL-5, IL-6 and MIP-3a were significantly suppressed in both ipsilateral and contralateral hemispheres of neonatal TBI rats compared to the control rats. A parallel study processing the plasma of the same cohort of neonatal rats revealed no difference in the same cytokines analyzed in the brain tissue, suggesting highly localized cytokine suppression in the brain during early injury. In stark contrast to the reported early pro-inflammatory response exhibited in adult TBI, the present neonatal TBI study demonstrated a reversed cytokine profile of downregulation. These results suggest a robust, immediate anti-inflammatory response mounted by the contralateral hemisphere of the young brain.

Vascular damage: a persisting pathology common to Alzheimer's disease and traumatic brain injury.

Alzheimer's disease (AD) and traumatic brain injury (TBI) are both significant clinical problems characterized by debilitating symptoms with limited available treatments. Interestingly, both neurological diseases are characterized by neurovascular damage. This impaired brain vasculature correlates with the onset of dementia, a symptom associated with hippocampal degeneration seen in both diseases. We posit that vascular damage is a major pathological link between TBI and AD, in that TBI victims are predisposed to AD symptoms due to altered brain vasculature; vice versa, the progression of AD pathology may be accelerated by TBI especially when the brain insult worsens hippocampal degeneration. Our hypothesis is supported by recent data reporting expedited AD pathology in presymptomatic transgenic AD mice subjected to TBI. If our hypothesis is correct, treatments targeted at repairing the vasculature may prove effective at treating both diseases and preventing the evolution of AD symptoms in TBI victims.

Diabetes insipidus contributes to traumatic brain injury pathology via CD36 neuroinflammation.

Each year, over one million people in the United States are affected by traumatic brain injury (TBI). Symptoms of both acute and chronic neuroinflammation follow TBI, coinciding with a robust immune response and activation of the brain's endogenous repair mechanisms. TBI can lead to endocrine failure as a result of damage to the thalamic region of the brain, evidenced by excessive thirst and polyuria often accompanying TBI. These symptoms indicate the presence of diabetes insipidus (DI), a disruption of water homeostasis due to antidiuretic hormone deficiency. This deficiency accompanies a mechanical or neuroinflammatory damage to the thalamic region during TBI, evidenced by increased expression of inflammatory microglial marker MHCII in this brain region. Excessive thirst and urinations, which are typical DI symptoms, in our chronic TBI rats also suggest a close connection between TBI and DI. We seek to bridge this gap between TBI and DI through investigation of the Cluster of Differentiation 36 (CD36) receptor. This receptor is associated with Low-Density Lipoprotein (LDL) deregulation, pro-inflammatory events, and innate immunity regulation. We posit that CD36 exacerbates TBI through immune activation and subsequent neuroinflammation. Indeed, scientific evidence already supports pathological interaction of CD36 in other neurological disorders including stroke and Alzheimer's disease. We propose that DI contributes to TBI pathology via CD36 neuroinflammation. Use of CD36 as a biomarker may provide insights into treatment and disease pathology of TBI and DI. This unexplored avenue of research holds potential for a better understanding and treatment of TBI and DI.