Table 2.
Overview of the main inter- and intracellular mechanisms of communication and their role in the response to plasma treatment.
| Molecule | Physiological Role(s) | Reported Response to Plasma | Redox Changes and Functional Consequences |
|---|---|---|---|
| Communication junctions | |||
| Ion channels | Ca2+-permeable and voltage-independent cation channels. Include transient receptor potential (TRP) channels. Auto- and paracrine cell–cell communication | Activated intracellular Ca2+ influx through TRP channels [203]. Induced Ca2+ release by ER* and mitochondria needed to induce senescence in melanoma cells [204] | ROS affect channel function, structure and downstream signalling pathways [205]. Can sense lipid oxidation [206]. Increased intracellular [Ca2+] by TRPC3 and TRPC4 leads to cell death upon oxidative stress [207]. H2O2 oxidizes TRPM2 and induces chemokine production [208]. TRP7 blockade induces apoptosis [209] |
| Pannexins (Panx) | Transmembrane proteins, form channels for the release of ATP and other metabolites [210]. Auto- and paracrine cell–cell communication | Unknown | Oxidative stress regulates Panx channel activation; ATP, ADP, and AMP release for apoptotic cell clearance [210]. Overexpression of Panx1 in cancer [211], its inhibition reduces tumour growth and invasiveness [212]. NO may inhibit Panx1 current [213] |
| Extracellular vesicles (EVs) | Secreted exosomes, microvesicles and apoptotic bodies [214]. Interact with adjacent or distant cells [215]. Para-, auto-, exo- and endocrine cell–cell communication | Increased number of EVs released by THP-1 and PMN* [216]. Less EVs produced by plasma-treated OVCAR-3 and SKOV-3 ovarian cancer cells [195]. Induced formation of apoptotic bodies [26,217,218] | Tumour cells produce high number of EVs with altered redox balance and ROS levels. EVs can scavenge/produce ROS and modify ROS content in target cells [219]. EVs involved in tumour development and metastasis [214] |
| Gap junctions (GJs) | Connect cells for electrical and metabolic (sugars, ions, amino acids, nucleotides) communication [220]. Auto- and paracrine communication | Plasma-generated ROS and intracellular ROS produced upon plasma treatment triggered bystander effect and damaged GJs [197] | Bystander effect: GJs can transmit ROS and cell death signals to neighbouring cells [196,221] |
| Connexins | Form gap junctions, transfer ions, small messengers, and metabolites. Forms hemichannels that communicate intra- and extracellular spaces [222] | Destroyed structure of connexins’ N-terminal tail [197]. Temporary loss of cell–cell contact [223]. Reduced Cx43 connexin expression in epithelial cells, transient increase of Cx43 in fibroblasts [187] | Redox status modulates the opening/closing and permeability of connexin hemichannels to NO and large molecules [224] |
| Tunnelling nanotubes (TnTs) | Long, filamentous, actin-based structures, connect cells to transfer drugs, organelles, nucleic acids, and proteins [225]. Cell–cell communication | Unknown | High H2O2 levels induce TnTs formation [226]. Propagation of death signal Fas ligand through TnTs between T cells [227]. TnTs mediate mitochondria transfer to rescue cells on oxidative stress [228]. Increased number of TnTs upon high oxidative stress [229] |
| Tight junctions (TJs) | Restrict diffusion based on size and charge to maintain homeostasis. TJs maintain cell surface polarity [230]. Cell–cell communication | Disrupted tight junctions in epithelial cells and caused retraction of Zonula occludens ZO-1 protein from cell membrane [231] | High doses of NO and H2O2 increases paracellular permeability in epithelial cells [232] |
| Claudins | Main structural TJs proteins. Block lipid and protein diffusion, ease transference of small ions [233] | Downregulated expression by repetitive exposure to plasma-treated medium [234] | ONOO‒ could interfere with claudin function [235]. Lipid peroxidation [236] and H2O2 can disrupt tight junctions [237] |
| Occludins | Contribute to TJ stability and barrier function [238] | Downregulated expression by repetitive exposure to plasma-treated medium [234] | Oxidative stress reduces occludin oligomerization [239], interaction with other TJ proteins and barrier tightness [240]. H2O2 induces occludins cleavage [241]; NO abolishes its immunoreactivity and redirects it to cytoplasm [240] |
| Anchoring junctions | |||
| Adherens | Homophilic lateral cell-to-cell adhesion via cadherin/catenin complex, transmit mechanical forces between cells, regulate signalling and transcription [242]. Required for TJs assembly [233] | Decreased E-cad expression [185,187]; function modulation, internalization in HaCaT cells [243]. Decreased E-cad in mice epidermis cells [243]. Increased E-cad expression in wounds of rats [244] and β-catenin expression in keratinocytes [234] | ROS selectively disrupts cadherin/catenin complexes [245,246], modulate receptors involved in cell-matrix and cell–cell adhesion [247]. Loss of E-cadherin activates EMT [248]. |
| Desmosomes | Intercellular junctions, link cells and stabilize the tissue structure [249]. Cell–cell adhesion | Increased the number of desmosomes in wounds [105] | ROS induce PKP3 phosphorylation, pPKP3 release from desmosome and desmosome instability [250]. Desmosomes are intracellular signal transducers in Wnt pathway [251] |
* ER = endoplasmic reticulum; PMN = polymorphonuclear leukocytes.