ID 19298 Poster Board 63 Background: Major Depressive Disorder (MDD) is a complex and heterogenous psychiatric disorder affecting more than 350 million people worldwide. Though the mechanisms underlying MDD are not fully understood, a subset of depressive patients can manifest chronic neuroinflammatory responses. In addition, brain-imaging studies in MDD patients have provided evidence of white matter reductions and such changes are hypothesized to lead to disruption of Oligodendroglial (OLN) homeostatic mechanisms, resulting in destabilization of emotional/cognitive circuitry. Recent work shows that a subset of OLN may adopt immune phenotypes (ImOL). The present goal of the study is to investigate whether these histopathological alterations are linked with chronic inflammation through a culture systems and a mouse model of depression.Methods In vivo: The Repeated Social Defeat Stress (RSDS) paradigm (10 days) was used to induce depressive-like behavior in 8-12-week-old male CX3CR1-GFP + and CSPG4-EGFP + mice. Behavioral tasks (BH) were performed to stratify the defeated mice to susceptible (S; depressive-like) and resilient (R; non-depressive) to stress groups. The study focuses on the stress-affected prefrontal cortex (mPFC) area. PLX5622 treatment was conducted for 7 days post RSDS. In vitro: Primary OPCs were isolated from neonatal (P1-P3) mouse pups. OPCs were treated with 100 U/mL IFNgfor 48 hours before being fixed or lysed. ResultsIn vivo: Our results show that microglia become activated, expressing higher levels of pro-inflammatory markers like iNOS and CD86 in S as compared to R and Control (C) mice. We have also demonstrated that in S mice, compared to C and R, hypomyelination occurs and O4+ OLN express MHCII, P2RY12, and C3, markers typically expressed by innate immune cells. Interestingly, when treated with PLX5622, all S mice become R. In line with this, inflammatory cytokines are decreased, numbers of ImOL are rescued to control levels and hypomyelination is rescued. In vitro: OPC culture work shows that IFNg treatment is enough to cause expression of MHCII in NG2+ OPCs.Conclusions Together, our computational data in MDD patients and depression mouse model, show that OLN can adopt an immune-like phenotype which is recued when 90-95% of microglia are ablated. Additionally, our culture work confirms that the ImOL phenotype does occur in response to inflammatory cytokines.
Tissue plasminogen activator (tPA) is a serine protease expressed in the mouse brain by neurons and immunocompetent microglia. Mice deficient in tPA exhibit resistance to excitotoxic neuronal injury and impaired microglial activation. tPA acts to activate microglia by interacting with annexinA2 on the surface of these cells. Activated microglia migrate to the sites of neuronal injury by following transient gradients of chemokines, one of which (that formed by monocyte chemoattractant protein-1, MCP-1, CCL2) is modulated by the presence of an active tPA/ plasmin proteolytic system. The tPA-mediated activation of mciroglia is followed by the upregulation of the inducible nitric oxide synthase (iNOS) that generates NO, which in the presence of an oxidative environment, is rapidly converted to peroxynitrite and modifies by nitrosylation proteins on neighboring neurons. Using molecular, pharmacological and genetic tools we investigate the involvement of tPA in different processes of the communication between neurons and microglia in physiology and pathology.
Tissue-type plasminogen activator (tPA) regulates vascular contractility through the low-density lipoprotein-related receptor (LRP) and this effect is inhibited by plasminogen activator inhibitor-1. We now report that tPA-mediated vasocontraction also requires the integrin avb3. tPA-induced contraction of rat aortic rings is inhibited by the RGD peptide and by monoclonal anti-avb3 antibody. tPA induces binding of LRP to avb3 in vascular smooth muscle cells. The three proteins are internalized within 10 minutes causing the cells to become refractory to re-addition of tPA. LRP and avb3 return to the cell surface by 90 minutes restoring cell responsiveness to tPA. PAI-1 and the PAI-1-derived hexapeptide EEIIMD abolish the vasocontracile activity of tPA and inhibit the tPA-mediated interaction between LRP and avb3. PAI-1, RGD and antibodies to both LRP and avb3 inhibit the effect of tPA on Ca++ mobilization in SMC. These data indicate that tPA-mediated vasocontraction involves the coordinated interaction of LRP with avb3. Understanding the mechanism underlying these interactions and the nature of the signals transduced may provide new tools to regulate vascular tone and other consequences of tPA-mediated signaling.
We are members of INDUCER- Increasing Diversity in Undergraduate Cancer Biology Education & Research. Our program strives to give opportunities to experience cancer research to underrepresented students interested in the biomedical sciences. We want to help bridge the gap in medicine between Caucasians and People of Color and combat racial disparity. We utilize the GL261 cell line in the murine model to study and understand glioblastomas and their tumor microenvironment, which includes microglia and macrophages. Microglia function as macrophages of the central nervous system, play a critical role in the innate and adaptive responses to pathogens and can take on a pro-inflammatory/anti-tumorigenic (M1) or anti-inflammatory/pro-tumorigenic (M2) phenotype. Our research introduces Colony Stimulating Factor 1 Receptor (CSF1R), which is expressed by both microglia and macrophages, whose signaling is critical for their proliferation and survival. Pexidartinib is a CSF1R inhibitor drug developed by Plexxikon Inc (PLX), a pharmaceutical company. They have generated PLX3397 and PLX5622. Each drug inhibits specific kinases, for example, PLX3397 inhibits c-KIT, CSF1R, and FLT3, which are key players in tumor proliferation, while PLX5622 is a specific inhibitor that only targets CSF1R signaling. Both PLX3397 and PLX5622, provided to mice in their chow, ablate microglia in the CNS of wild type mice, without affecting peripheral macrophages. Upon discontinuation of the diet, microglia repopulate the CNS. PLX73086 is a second generation CSF1R inhibitor, and little is known about its effects on microglia and macrophages. What is known is that it should only ablate macrophages in the periphery, not affecting the CNS because it is not expected to cross the Blood Brain Barrier. Upon the discontinuation of the diet, repopulation is similarly expected. In our research, we studied the effects of PLX73086 on macrophages and microglia of the murine glioma model, after being fed the diet for 7 days and 7 days off the diet. We compared the extent of ablation and repopulation of the tissue. Citation Format: Maryam Tayyab, Maame Gyamfi, Michael Caponegro, Dr. Styliani-Anna (Stella) Tsirka. Investigating the Interplay of monocytes in the tumor microenvironment of glioblastomas [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D065.
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