Abstract WP308: Role of Microthrombi and Vasospasm in the Development of Delayed Neurological Deficits After Subarachnoid Hemorrhage in Mice

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Devin W McBride ◽  
Ari Dienel ◽  
Remya A Veettil ◽  
Kanako Matsumura ◽  
Peeyush Kumar T. ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Mouse Model ◽  
Experimental Studies ◽  
Brain Slices ◽  
Neurological Deficits ◽  
Male Mice ◽  
Male And Female ◽  
Delayed Neurological Deterioration ◽  
First Time

Rationale: Microthrombosis has been suggested as a major factor contributing to delayed neurological deterioration in patients after subarachnoid hemorrhage (SAH). However, experimental studies on the role of microthrombi in delayed deficits after SAH has not been investigated. Our hypothesis is that, following SAH, mice which develop delayed neurological deficits have a greater number of microthrombi than mice which do not develop delayed neurological deficits. Methods: SAH was induced in adult male and female C57BL/6 mice via endovascular perforation. Mice were randomly assigned into sham (n=6/sex) or SAH groups (n=22-24/sex). Neurobehavior was performed on days 1-3, 5, and 7 post-SAH using a composite neuroscore. Animals were sacrificed on the day of delayed deficits or 7 days post-SAH. Microthrombi count and vessel diameters (for vasospasm) were measured using H&E stained brain slices. All outcomes were performed and all data were analyzed by a blinded investigator. Results: Seventeen percent (4/24) of male mice and thirty-six percent (8/22) of female mice developed delayed deficits on days 3-5 post-SAH (Figures 1A and 1B). Those mice which developed delayed deficits had significantly more microthrombi in their brains than mice which did not develop delayed deficits; vasospasm did not correlate with delayed deficits. Additionally, female SAH mice develop delayed deficits at a higher frequency than males (Figure 1C). Conclusions: This work shows for the first time delayed deficits in a SAH mouse model. Further, microthrombi correlated with delayed deficits, whereas no correlation was between delayed deficits and vasospasm. The data within this study suggests that preventing microthrombi may improve functional recovery and reduce the risk of delayed deficits.

scholarly journals Long-term decreased cannabinoid type-1 receptor activity restores specific neurological phenotypes in the Ts65Dn mouse model of Down syndrome

2021 ◽  
Author(s):  
Anna Vazquez-Oliver ◽  
Silvia Perez-Garcia ◽  
Nieves Pizarro ◽  
Laura Molina-Porcel ◽  
Rafael de la Torre ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Side Effects ◽  
Mouse Model ◽  
Neurological Deficits ◽  
Wild Type ◽  
Male And Female ◽  
Cannabinoid Type 1 Receptor ◽  
Cognitive Improvement

Intellectual disability is the most prevalent and limiting hallmark of Down syndrome (DS), without any pharmacological treatment available. Neurodegeneration and neuroinflammation are relevant neurological features of DS reaching to early development of Alzheimer s disease. Preclinical evidence suggests that the endocannabinoid system, an important neuromodulator on cognition and neuroinflammation, could act as beneficial target in DS. Indeed, cannabinoid type-1 receptor (CB1R) activity was enhanced in the hippocampus of young-adult trisomic Ts65Dn mice, a well-characterized surrogate model of DS. In previous studies, inhibition of CB1R, was able to restore key neurological deficits in this mouse model. To determine the possible clinical relevance of this target, it is mandatory to evaluate the long-term consequences of attenuated CB1R activity and to minimize the possible side-effects associated to this mechanism. We found that CB1R expression was significantly enhanced in the hippocampus brains of aged DS subjects. Similarly, middle-aged trisomic mice showed enhanced CB1R expression. Long-term oral administration of a low dose of the CB1R specific antagonist rimonabant was administered to male and female Ts65Dn trisomic and wild-type mice from the time of weaning to 10 months, an age when signs of neurodegeneration have been described in the model. CB1R inhibition resulted in significant cognitive improvement in novel object-recognition memory in trisomic male and female mice, reaching a similar performance to that of wild-type littermates. Interestingly, this long-term rimonabant treatment modify locomotor activity, anxiety-like behavior, body weight or survival rates. Brain analysis at 10 months of age revealed noradrenergic and cholinergic neurodegeneration signs in trisomic mice that were not modified by the treatment, although the alterations in hippocampal microglia morphology shown by vehicle-treated trisomic mice was normalized in trisomic mice exposed to rimonabant. Altogether, our results demonstrate a sustained pro-cognitive effect of CB1R inhibition at doses that do not produce major side effects that could be associated to an anti-inflammatory action, suggesting a potential interest in this target of to preserve cognitive functionality in DS.

Abstract 285: Osteopontin Deficiency Ameliorates Heart Failure with Preserved Ejection Fraction Pathology by Upregulating Mitochondrial 2-Oxoglutarate Dehydrogenase Like Enzyme

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Keyvan Yousefi ◽  
Wen Ding ◽  
Lina A Shehadeh
Keyword(s):  
Mouse Model ◽  
Diastolic Dysfunction ◽  
Interstitial Fibrosis ◽  
Matricellular Protein ◽  
Double Knockout ◽  
Protein Levels ◽  
Lower Protein ◽  
Myocardial Energetics ◽  
First Time

HFpEF is an increasingly prevalent syndrome associated with impaired myocardial energetics, for which no etiologic therapy is available. Osteopontin (OPN) is a matricellular protein that is upregulated in the circulation of HFpEF patients, and reported to induce mitochondrial stress in rodent cardiomyocytes. Here we evaluate the role of circulating OPN in regulating myocardial function in the nephrotic Col4a3 -/- mouse model of HFpEF. We performed extensive cardiac, biochemical and mitochondrial analyses of the Col4a3 -/- mouse and found a striking HFpEF phenotype. We showed OPN levels were elevated in Col4a3 -/- mice (FC=2.1, n=6; p<.01). Col4a3 -/- mice were hypertensive, had diastolic dysfunction, myocyte hypertrophy and interstitial fibrosis - all of which were ameliorated in Col4a3 -/- OPN -/- mice (n=5-20; p<.05). Col4a3 -/- hearts had dysmorphic mitochondria (EM), lowered antioxidant capacity as a 50% reduction in GSH/GSSG ratio (n=6; p<.05) and lower protein levels of mitochondrial respiratory complexes I, II and IV (p<.05). Flux assay in adult cardiomyocytes showed that maximal respiration was reduced in Col4a3 -/- hearts (575.84±37.6 vs 322.34±25.48 pmol/min in WT, n=9; p<.0001). Microarray data (validated by mitochondrial blot) implicated OGDHL as decreased in Col4a3 -/- hearts but increased in double knockout Col4a3 -/- OPN -/- hearts compared to WT (n=3; p<.05). OGDH activity was also lower in Col4a3 -/- hearts (17.1±7.3 vs 2.5±1.1 mU/mg in WT; n=6; p<.05). In Col4a3 -/- mice, heart-specific AAV9-mediated overexpression of OGDHL, similar to global OPN KO, improved survival by ~50-100% (p<.0001). Isovolumetric relaxation time, a marker of diastolic dysfunction, which is prolonged in Col4a3 -/- mice (26.17 vs 15.30±1 ms, n=26; p<.001) was decreased in Col4a3 -/- OPN -/- mice (18.1±1 ms, n=37; p<.01) as well as in AAV9-cTnT-OGDHL-treated Col4a3 -/- mice (16.7±2.5 ms, n=8; p<.05). In conclusion, we present a new mouse model for HFpEF in which diastolic function and lifespan can be improved by genetic deletion of OPN or cardiac OGDHL gene therapy. Our results elucidate for the first time the pivotal roles of circulating OPN and cardiac OGDHL in HFpEF pathophysiology and present two related potential therapeutic targets for HFpEF.

scholarly journals ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model

2019 ◽  
Vol 20 (20) ◽  
pp. 5151 ◽  
Author(s):  
Norante ◽  
Peggion ◽  
Rossi ◽  
Martorana ◽  
De Mario ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Nervous System Function ◽  
Serca Pump ◽  
Selective Death ◽  
First Time ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.

scholarly journals Role of Tumor Associated Fibroblasts in Human Liver Regeneration, Cirrhosis, and Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Daniela Cesselli ◽  
Antonio Paolo Beltrami ◽  
Alessandra Poz ◽  
Stefania Marzinotto ◽  
Elisa Comisso ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Human Liver ◽  
Adult Stem Cells ◽  
Experimental Studies ◽  
Tumor Cell Lines ◽  
Liver Scan ◽  
First Time

Tumor associated fibroblasts (TAFs) are considered a microenvironmental element critical for tumor growth and progression. Experimental studies suggest that their origin could be from mesenchymal stem cells (MSCs) derived from the bone marrow. However, the role played by TAFs in cirrhosis, hepatocellular carcinoma development, and progression is largely unknown, andin vitrohuman models are missing. This paper for the first time demonstrates that (1) human neoplastic livers possess a population of multipotent adult stem cells (MASCs) with properties of TAFs; (2) a population of MASC-derived TAFs is already present in cirrhotic, not yet neoplastic, livers; (3) MASCs isolated from nonneoplastic and noncirrhotic liver scan acquire a TAF phenotype when grown in a medium conditioned by tumor cell lines, supporting the notion that TAF could originate from resident primitive cells (MASCs), possibly through a paracrine mechanism.

The Targeted Disruption of Kdm6a/Utx in Mice Has Gender-Dependent Effects on Primitive Hematopoietic Cell Populations and Myeloid Progenitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1158-1158
Author(s):  
Ling Tian ◽  
Lukas D. Wartman
Keyword(s):  
Bone Marrow ◽  
Young Female ◽  
Conditional Knockout ◽  
Cell Populations ◽  
Male Mice ◽  
Male And Female ◽  
Myeloid Progenitor ◽  
Cell Counts ◽  
Histone H3k27

Abstract Putative inactivating mutations of EZH2 (the histone H3K27 methylase) and KDM6A (a histone H3K27 demethylase) both occur in myeloid malignancies, including acute myeloid leukemia (AML). The mechanism(s) by which genetic inactivation of KDM6A contributes to leukemogenesis is not clear, and the role of KDM6A in normal hematopoiesis is largely undefined. To address the role of KDM6A in hematopoiesis, we generated a conditional knockout mouse of the Kdm6a gene on the X chromosome (with LoxP sites flanking the 3rd exon) and crossed these mice with Vav1-Cre transgenic mice to inactivate Kdm6a in hematopoietic stem/progenitor cells. Mice were born in expected Mendelian ratios with no aberrant phenotypic abnormalities. We characterized normal hematopoiesis from young (6 to 8 week old) male and female Kdm6a conditional KO mice crossed with Vav1-Cre mice. We included both male and female (both homozygous and heterozygous Kdm6a KO mice) animals, since Kdm6a can have gender dependent effects, and human UTY (the KDM6A homologue on the Y chromosome) does have H3K27 demethylase activity (Thieme S et al., Blood, 2012 and Walport, L.J. et al., J Biol Chem, 2014). Young female Kdm6a null mice had a mild thrombocytopenia relative to all other cohorts with an average platelet count of 423 K/uL +/- 48 (n=10) vs. 794 K/ul +/- 76 for the WT littermates (n=10), p=0.006. We also observed mild splenomegaly in both the male and female Kdm6a null mice. The splenomegaly was not associated with extramedullary hematopoiesis or a shift in progenitor or mature lineage cell populations within the spleen. There was no difference in other blood cell counts, bone marrow cellularity, body weight or thymus weight between cohorts of young mice. We did not detect significant differences in the global levels of 21 histone H3 or 10 histone H4 modifications, using a multiplex colorimetric assay from lysates of whole bone marrow obtained from these mice. However, using western blotting, we did observe a decrease in H3K27 acetylation in both male and female Kdm6a null mice. We detected an aberrant self-renewal phenotype that may be relevant for leukemogenesis, which is in contrast to a previously reported impaired colony-forming ability using a knockdown approach of Kdm6a (Liu J et al., Exp Hematol, 2012). Using a serial replating assay with myeloid progenitor conditions, we found that both male and female Kdm6a null mice produced significantly more colonies in the second round of replating relative to control mice. Moreover, the homozygous female Kdm6a null mice had a significantly increased number of colonies at week 2, compared to hemizygous male mice (note that both are deficient for Kdm6a, but the male mice may compensate for it because of Uty). Flow cytometry revealed a slight myeloid skewing in the bone marrow of young female and male Kdm6a null mice with increased numbers of Gr-1+ and Cd11b+ cells. We did not detect differences in other lineages except for a slight decrease in erythroid precursors (as determined by Ter119 staining) in Kdm6a null mice. We also quantified the primitive hematopoietic and myeloid progenitor subpopulations from the bone marrow of these mice. Young female Kdm6a null mice had a significant decrease in the KLS population, which contained a lower frequency of short-term HSCs and multipotent progenitors. We also detected a significant decrease in MEPs (consistent with the observed thrombocytopenia). In young male Kdm6a null mice, the KLS population is not altered. A competitive transplant experiment validated the known engraftment defect in female Kdm6a null donor mice (Thieme S et al., Blood, 2012). Finally, we established a tumor watch consisting of female and male Kdm6a conditional KO mice and their littermate controls. After 18 months of follow-up, we did not observe the development of leukemia or other overt hematologic disease in either male or female mice deficient for Kdm6a, compared to a previous report that suggested that the rapid development of myelodysplasia (Thieme S et al., Blood, 2012). The difference in phenotype may be explained by cell-autonomous vs. non-autonomous effects (inactivation of Kdm6a in our model is essentially limited to the hematopoietic compartment). In sum, our data suggest that Kdm6a has a relatively subtle role in normal hematopoiesis, but the perturbations associated with its inactivation reveal insights into its role as a potential tumor suppressor in myeloid leukemogenesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Ornithine decarboxylase antizyme in kidneys of male and female mice

1988 ◽  
Vol 254 (2) ◽  
pp. 367-372 ◽  
Author(s):  
Y Murakami ◽  
M Marumo ◽  
S I Hayashi
Keyword(s):  
Ornithine Decarboxylase ◽  
Half Life ◽  
Mouse Kidney ◽  
Repeated Injection ◽  
Male Mice ◽  
Protein Inhibitor ◽  
Male And Female ◽  
Female Mice ◽  
Htc Cells

Antizyme, a protein inhibitor of ornithine decarboxylase (ODC), was shown to be induced in mouse kidney by repeated injection of putrescine. Antizyme was also present as a complex with ODC in the kidney of untreated mouse. The amount of the renal ODC-antizyme complex was 3-fold higher in male mice than in female mice. On the contrary, the proportion of ODC present as a complex with antizyme was 24-fold higher in females than in males, and the decay of renal ODC activity after cycloheximide treatment was about 5-fold more rapid in females than in males. Administration of testosterone to female mice, a procedure known to prolong the half-life of renal ODC, increased both ODC activity and the content of ODC-antizyme complex, but decreased the antizyme/ODC ratio in the kidney. These results are consistent with the previous observation in HTC cells that the decay rate of ODC activity in the presence of cycloheximide correlated well with the proportion of ODC present as a complex with antizyme, suggesting the ubiquitous role of antizyme in ODC degradation.

scholarly journals ZAP-70 Expression in Non Tumoral B Cells: Role in B Tolerance Breakdown?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1114-1114
Author(s):  
Mickaël Martin ◽  
Anne Marie Knapp ◽  
Dana Ghergus ◽  
Fabien Delmotte ◽  
Laurent Vallat ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Rt Pcr ◽  
Variable Regions ◽  
Conditional Expression ◽  
Bcr Signaling ◽  
Tolerance Breakdown ◽  
First Time

Abstract Abnormal expression of the tyrosine kinase ZAP-70 by tumoral B cells in chronic lymphocytic leukemia (CLL) is associated with bad prognosis, related to B cell receptor (BCR) hypersignalling, clonal expansion and autoimmune cytopenia (AIC) occurrence, these latter being mostly induced by polyclonal IgG from the residual non tumoral B cells. We previously shown that ZAP-70 is expressed by these non tumoral B cells in CLL, positively associated with its expression in CLL B cells and with AIC occurrence (Ghergus et al. Poster ASH 2017). Here, we show for the first time a potential role of ZAP-70 expression in tolerance breakdown in CLL and in an original knock in mouse model overexpressing ZAP-70 conditionally in B cells. First, to assess a potential molecular link between ZAP-70+ CLL and non tumoral B cells, an analysis of their BCR repertoire has performed on FACS-sorting CD19+CD5-IgM-IgD- (non tumoral) and CD19+CD5+IgM-IgD- (tumoral) single B cells from blood samples of CLL patients with AIC. ZAP-70 positivity was screened by RT-PCR, and variable regions of heavy (IGVH) and light (IGVK/VL) immunoglobulin genes amplified by RT-PCR on ZAP-70+ cells. To date, analysis of 24 BCR sequences from 7 patients showed that non tumoral ZAP-70+ B cells were polyclonal, without stereotypy, using different V(D)J and CDR3 in comparison with those of the corresponding CLL B cells. IGVH of non tumoral ZAP-70+ B were mostly mutated, of replacement type, suggesting antigenic contact, contrary to CLL B cells. To determine potential autoreactivity of the non-tumoral ZAP-70+ B cells, IGVH and corresponding IGVK/VL were amplified for production of recombinant antibodies (rAb). To date, among 17 rAB from 7 different patients, 2/13 (15.4%) have an antinuclear autoreactivity on HEp-2 cells and 4/17 (23.5%) were polyreactive on ELISA (DNA, lipopolysaccharide, insulin), compared respectively to 6% and 4,3% of control B cells (Wardemann et al., Science 2003). Production of 7 additional rAb and tests for anti-erythrocytes and anti-platelets reactivity are in process. To study functional consequences of early ZAP-70 expression in B cells in vivo, we generated a knock in Zap-70+/Mb1-Cre+mouse model (KI ZAP), to induce conditional expression of ZAP-70 in the B cell compartment from the proB stage, with KI Zap-70+/Mb1-Cre-mice as controls (CTRL). The ZAP-70 mRNAs levels in B cells from KI ZAP mice were on average 20 times higher than that in CTRL B cells. Up to 20 months-old, KI ZAP mice did not develop signs of lymphoproliferation. KI ZAP mice had hypo-IgG since 16 weeks-old (p<0.001) together with hypo-IgM from 14 months-old (p<0.01). Immunophenotyping revealed a reduction in mature naive, mature switched as well as in germinal center B cells (p<0.001, p=0.002 and p<0.01 respectively) and a trend for plasma cells (p=0.07). Microarrays showed enrichment in circulating IgG and IgM autoantibodies against various antigens in KI ZAP mice. These mice had reduced apoptosis rates of proB (p<0.01), preB (p=0.02), and immatures B cells (p=0.03), together with enrichment in marginal zone (p=0.01), trend for transitional T2/T3, and reduction in B1a cells (p<0.01). After immunization by ovalbumin + Freund's adjuvant, a reduced production of specific IgG and IgM was observed (p=0.01 and p=0.03 respectively) with a trend in decreased number of antibody-secreting cells (p=0.07). KI ZAP B cells shown increased spontaneous activation and proliferation levels holding after BCR stimulation (p<0.01), as well as an increased intracellular calcic flow (p<0.001). Preliminary data suggested a reduced SYK phosphorylation after BCR stimulation in KI ZAP B cells. Our findings highlight for the first time that non tumoral B cells ZAP-70+ are distinct from CLL cells at cellular level, but probably enriched in autoreactive cells. Moreover, we shown that early ZAP-70 expression in normal B cells in vivois associated with autoimmune characteristics, together with partial block in B cells peripheral maturation, and a conversely early increased activation and proliferation status. ZAP-70 could interfere early with SYK leading to an altered BCR signaling responsible for defect in normal B maturation promoting emergence of autoreactive B cells. Mechanistic role of ZAP-70 in BCR signaling has to be further analyzed but our data open new opportunities involving ZAP-70 in the understanding of B cell development and physiopathology of tolerance breakdown. Disclosures No relevant conflicts of interest to declare.

scholarly journals Microthrombi Correlates With Infarction and Delayed Neurological Deficits After Subarachnoid Hemorrhage in Mice

Stroke ◽  
2020 ◽  
Vol 51 (7) ◽  
pp. 2249-2254 ◽  
Author(s):  
Ari Dienel ◽  
Remya Ammassam Veettil ◽  
Sung-Ha Hong ◽  
Kanako Matsumura ◽  
Peeyush Kumar T. ◽  
...  
Keyword(s):  
Sex Differences ◽  
Subarachnoid Hemorrhage ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Behavioral Performance ◽  
Large Artery ◽  
Male Mice ◽  
Functional Deficits ◽  
Female Mice ◽  
Correlation Analyses

Background and Purpose: Delayed neurological deficits are a devastating consequence of subarachnoid hemorrhage (SAH), which affects about 30% of surviving patients. Although a very serious concern, delayed deficits are understudied in experimental SAH models; it is not known whether rodents recapitulate the delayed clinical decline seen in SAH patients. We hypothesized that mice with SAH develop delayed functional deficits and that microthrombi and infarction correlate with delayed decline. Methods: Adult C57BL/6J mice of both sexes were subjected to endovascular perforation to induce SAH. Mice were allowed to survive for up to 1 week post-ictus and behavioral performance was assessed daily. Postmortem microthrombi, large artery diameters (to assess vasospasm), and infarct volume were measured. These measures were analyzed for differences between SAH mice that developed delayed deficits and SAH mice that did not get delayed deficits. Correlation analyses were performed to identify which measures correlated with delayed neurological deficits, sex, and infarction. Results: Twenty-three percent of males and 47% of females developed delayed deficits 3 to 6 days post-SAH. Female mice subjected to SAH had a significantly higher incidence of delayed deficits than male mice with SAH. Mice that developed delayed deficits had significantly more microthrombi and larger infarct volumes than SAH mice that did not get delayed deficits. Microthrombi positively correlated with infarct volume, and both microthrombi and infarction correlated with delayed functional deficits. Vasospasm did not correlate with either infarction delayed functional deficits. Conclusions: We discovered that delayed functional deficits occur in mice following SAH. Sex differences were seen in the prevalence of delayed deficits. The mechanism by which microthrombi cause delayed deficits may be via formation of infarcts.

scholarly journals IL (Interleukin)-15 Bridges Astrocyte-Microglia Crosstalk and Exacerbates Brain Injury Following Intracerebral Hemorrhage

Stroke ◽  
2020 ◽  
Vol 51 (3) ◽  
pp. 967-974 ◽  
Author(s):  
Samuel X. Shi ◽  
Yu-Jing Li ◽  
Kaibin Shi ◽  
Kristofer Wood ◽  
Andrew F. Ducruet ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Autologous Blood ◽  
Brain Slices ◽  
Neurological Deficits ◽  
Transgenic Mouse Line ◽  
Il Interleukin ◽  
Targeted Expression ◽  
Interleukin 15

Background and Purpose— Microglia are among the first cells to respond to intracerebral hemorrhage (ICH), but the mechanisms that underlie their activity following ICH remain unclear. IL (interleukin)-15 is a proinflammatory cytokine that orchestrates homeostasis and the intensity of the immune response following central nervous system inflammatory events. The goal of this study was to investigate the role of IL-15 in ICH injury. Methods— Using brain slices of patients with ICH, we determined the presence and cellular source of IL-15. A transgenic mouse line with targeted expression of IL-15 in astrocytes was generated to determine the role of astrocytic IL-15 in ICH. The expression of IL-15 was controlled by a glial fibrillary acidic protein promoter (GFAP-IL-15 tg ). ICH was induced by intraparenchymal injection of collagenase or autologous blood. Results— In patients with ICH and wild-type mice subjected to experimental ICH, we found a significant upregulation of IL-15 in astrocytes. In GFAP-IL-15 tg mice, we found that astrocyte-targeted expression of IL-15 exacerbated brain edema and neurological deficits following ICH. This aggravated ICH injury in GFAP-IL-15 tg mice is accompanied by increased microglial accumulation in close proximity to astrocytes in perihematomal tissues. Additionally, microglial expression of CD86, IL-1β, and TNF-α is markedly increased in GFAP-IL-15 tg mice following ICH. Furthermore, depletion of microglia using a colony stimulating factor 1 receptor inhibitor diminishes the exacerbation of ICH injury in GFAP-IL-15 tg mice. Conclusions— Our findings identify IL-15 as a mediator of the crosstalk between astrocytes and microglia that exacerbates brain injury following ICH.

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