Stem Cell Reviews and Reports | 2021
Targeting the PANoptosome with miRNA Loaded Mesenchymal Stem Cell Derived Extracellular Vesicles; a New Path to Fight Against the Covid-19?
Abstract
Coronavirus disease 19 (Covid-19), as announced on March 11, 2020, is a pandemic caused by the SARS-CoV-2 virus that affects the whole world and can cause fatal consequences [1]. Common clinical findings of Covid-19 includes fever, dry cough, fatigue, headache, dizziness, abdominal pain, nausea, vomiting, anosmia, dysgeusia, and diarrhea. Depending on the severity of the disease, clinical signs of coagulation defects, cardiac dysfunction, liver injury, renal dysfunction may develop. Reductions in total lymphocytes, CD4 + and CD8 + T-cells, B-cells, and natural killer cells, elevations in D-dimer levels, C-reactive protein (CRP), lactate dehydrogenase (LDH), and high-sensitivity cardiac troponin I and ground-glass opacities in computed tomography are laboratory findings of the disease [2]. Inappropriate immune system activation and cytokine storm can also be seen in the later stages of the disease [3]. It is known that different viruses, fungi and bacteria activate inflammatory cell death pathways so far [4]. PANoptosis is a new concept that has emerged recently and refers to the combined activation of inflammation-mediated pyroptosis, apoptosis and necroptosis-type cell death processes through PANoptosome [5, 6]. This cellular process may explain the link between tissue damage, reduced number of immune cells and inappropriate immune system activation seen in Covid-19. PANoptosome consists of Caspases 1/6/8, NLR Family Pyrin Domain Containing 3 (NLRP3), Apoptosis-Associated Speck-Like Protein Containing A CARD (ASC), Receptor Interacting Serine/Threonine Kinase 1/3 (RIPK1/3) and ZDNA Binding Protein 1 (ZBP1) proteins [7]. In the inflammasome induced PANoptosis process, pyroptosis, apoptosis and necroptosis is executed through Gasermin D (GSDMD), Caspases 3/6/7 and Mixed Lineage Kinase Domain-Like Protein (MLKL) proteins, respectively [8]. Although Lee et al. stated that SARS-CoV-2 infection does not activate necroptosis arm of the PANoptosis there are also publications suggesting the opposite [9]. The study conducted by Zheng et al., and observed that PANoptosis is induced by NLRP3 in bone marrow-derived macrophages infected with Murine Hepatitis Virus, which is murine corona virus, shows that corona viruses can induce PANoptosis [10]. Also in another report it was stated that cytokines TNF-α and IFN-γ, which are related to SARS-CoV-2 infection, stimulated the pyroptosis, apoptosis, and necroptosis pathways with a synergistic effect in mouse bone marrow derived macrophages while blokage of Signal Transducer And Activator Of Transcription 1 (STAT1) / Interferon Regulatory Factor 1n (IRF1) pathway suppressed PANoptosis [11]. In some studies on Covid-19 patients, it was determined that cell death pathways are activated in different types of cells. It is known that apoptosis is increased in B and T-cells in the peripheral blood of Covid-19 patients and it is associated with the disease severity [12, 13]. Li et al., reported that, in the lung biopsy materials obtained from two patients apoptosis and pyroptosis increased in type 1 and 2 pneumocyte and endothelial cells [14]. It has also been shown that inflammation-mediated pyroptosis is activated in monocytes infected with SARS-CoV-2 and in monocytes of Covid-19 patients [15]. Also in some reports it was reported that, PANoptosome components were overexpressed or activated in cells of Covid-19 patients. In a report it was suggested that the level of RIPK3 in the peripheral blood of patients with a severe course of Covid-19 was higher compared to patients with a mild course [16]. One of the components of the PANoptosome complex is NLRP3. Analysis of SARS-Cov2 infected Calu-3 lung epithelial cells and lung tissue of patients who died due to Covid-19 showed that apoptotic and necroptotic pathways were activated by NLRP3 and Caspase 8 [17]. Studies conducted in peripheral blood mononuclear * Zafer Çetin [email protected]