The Immunomodulatory Role of Cell-Free Approaches in SARS-CoV-2-Induced Cytokine Storm—A Powerful Therapeutic Tool for COVID-19 Patients

Abstract

Currently, there is still no effective and definitive cure for the coronavirus disease 2019 (COVID-19) caused by the infection of the novel highly contagious severe acute respiratory syndrome virus (SARS-CoV-2), whose sudden outbreak was recorded for the first time in China in late December 2019. Soon after, COVID-19 affected not only the vast majority of China’s population but the whole world and caused a global health public crisis as a new pandemic. It is well known that viral infection can cause acute respiratory distress syndrome (ARDS) and, in severe cases, can even be lethal. Behind the inflammatory process lies the so-called cytokine storm (CS), which activates various inflammatory cytokines that damage numerous organ tissues. Since the first outbreak of SARS-CoV-2, various research groups have been intensively trying to investigate the best treatment options; however, only limited outcomes have been achieved. One of the most promising strategies represents using either stem cells, such as mesenchymal stem cells (MSCs)/induced pluripotent stem cells (iPSCs), or, more recently, using cell-free approaches involving conditioned media (CMs) and their content, such as extracellular vesicles (EVs) (e.g., exosomes or miRNAs) derived from stem cells. As key mediators of intracellular communication, exosomes carry a cocktail of different molecules with anti-inflammatory effects and immunomodulatory capacity. Our comprehensive review outlines the complex inflammatory process responsible for the CS, summarizes the present results of cell-free-based pre-clinical and clinical studies for COVID-19 treatment, and discusses their future perspectives for therapeutic applications.

Regulation of immune responses to infection through interaction between stem cell-derived exosomes and toll-like receptors mediated by microRNA cargoes

“…These miRNAs can decrease the production of inflammatory cytokines and minimize cell death by targeting the corresponding 3′-UTRs of multiple mRNAs and TLR pathways such as TLR7/NF-kB signaling. In general, the mechanism of exosomal miRNAs effect on cytokine storm in COVID-19 take place in different ways, the most important of which is to reduce the level of chemokines and pro-inflammatory cytokines through the release of IL-1 receptor agonist, secreting the anti-inflammatory protein TNF-α–stimulated gene 6 protein (TSG-6), and finally, downregulating NF-kB signaling in a TLRs-dependent signaling pathway ( Kiaie et al., 2021 ; Csobonyeiova et al., 2023 ). On the other hand, it has also been shown that the use of miRNA can be effective in controlling HIV infections.…”

Potential therapeutic effects and nano-based delivery systems of mesenchymal stem cells and their isolated exosomes to alleviate acute respiratory distress syndrome caused by COVID-19

“…This enables them to cross the blood-brain barrier, thereby preventing the occurrence of pulmonary embolism following transplantation of MSCs [ 109 ]. Interestingly, MSC-exosomes can be used as nanocarriers to deliver antiviral drugs and anti-inflammatory agents [ 110 ]. Hence, they are regarded as a nanoscale delivery platform for microRNAs, which by nature may target and modify genes associated with the cytokine storm, a severe immune response found in COVID-19 patients [ 111 ].…”

Macrophage membrane-coated nanoparticles for the treatment of infectious diseases

“…Specifically, when infection occurs in the body, they are recruited to the damaged site via interactions between chemokines and chemokine receptors [17]. Subsequently, Toll-like receptors (TLRs) on the macrophage surface can recognize pathogens via pathogen-associated molecular patterns (PAMPs), leading to macrophage activation [18,19]. Activated macrophages serve in removing pathogens and cell debris and present antigens to T cells to drive the adaptive immune response [18].…”

“…Subsequently, Toll-like receptors (TLRs) on the macrophage surface can recognize pathogens via pathogen-associated molecular patterns (PAMPs), leading to macrophage activation [18,19]. Activated macrophages serve in removing pathogens and cell debris and present antigens to T cells to drive the adaptive immune response [18]. In addition, macrophages are regulated via interactions between multiple cytokines and cytokine receptors on their membranes, resulting in phenotypic changes [20].…”