4. Innate Immunity-Mediated Phenoptosis as a Common Cause of Human Mortality
In the previous sections we have emphasized that manifestations of innate immunity mechanisms in many pathological conditions led to death even when the pathological agents (viruses or bacteria) cannot cause death per se. We also showed that such fatalities could be prevented by interfering, in diverse ways, with the specific innate immunity regulatory pathways controlled by mitochondria. In addition, it was demonstrated that the probability of death outcome (from all causes) correlates with the presence of certain blood biomarkers most of which are related to inflammation.
Up to now, the above-described fatalities were attributed to the imperfection of the innate immunity system causing its overreaction. However, the respective mortality rates are very high, up to 50% in the case of sepsis, even in the best intensive care units around the world. High mortality is also inherent in various pathologies associated with local inflammation (ischemic and toxic lesions of the brain, heart, kidneys, liver, etc.), and in some pathologies where inflammation is not clearly expressed, but DAMP plays an important role in pathogenesis (including aforementioned neurodegenerative diseases). Such extremely high, seemingly wanton mortality must have an evolutionary cause. More likely is that (i) the high mortality, as caused by sepsis, sterile systemic inflammation, and some described severe infections, is a manifestation of phenoptosis that aims at cleansing the population of unwanted individuals, and (ii) innate immunity reactions are in a similar way involved in all the above-described cases because phenoptosis uses them as an executive mechanism. Involvement of the same innate immunity pathways, under certain circumstances leading to death, explains the similarity of symptoms in the generalized, pathogen-induced inflammation including sepsis and in sterile types of inflammation.
Cancers also fit into this framework. As early as in 1994, Sommer suggested that cancer “has a biological role in that it mediates evolutionary selection for a constant rate of germline mutation” (quoted from
[57][149])
[1]. Cancer can be one of the most important mediators of negative selection, not only in the case of mutations (germline, as well as somatic), as discussed by Sommer
[57][149], but also in pathologies related to systemic inflammation. Although it was repeatedly shown that inflammation can provoke cancer, inflammation plays a dual role in cancer
[58][150]. On the one (dark) side, DAMPs released from tumors during progression or as a result of therapy can directly promote invasion and metastasis by interacting with PRRs expressed on tumor cells
[59][60][151,152]. Moreover, DAMP-induced chronic inflammation in the tumor microenvironment attracts immunosuppressive cells such as M2 macrophages, myeloid suppressor cells and regulatory T cells, helping tumors escape immunosurveillance
[61][153]. On the other (bright) side, DAMPs contribute to immunogenic tumor cell death caused by conventional therapy or modern cancer immunotherapy
[51][45].
Generally, the existence of specific phenoptotic programs is indicated by the observations that such non-trivial symptoms as thrombosis and vascular leakage, hemorrhage, and organ failure were observed in relation to quite different causes, such as influenza, COVID-19, and some other respiratory viral infections, as well as in bacterial pneumonia, cholera and so on
[62][63][64][69,154,155].
The existence of a distinct program gives a hope of preventing phenoptosis by interfering with the checkpoints of the program. Involvement of mitochondria as one of such checkpoints explains the aforementioned therapeutic effects of mitochondria-targeted antioxidants and very long chain 3-omega fatty acids in a variety of severe pathologies. It is noteworthy, that the impact of mitochondria-targeted antioxidants and very long chain 3-omega fatty acids is not just beneficial, but life-saving. Specifically, SkQ1-type antioxidants were the first to show a decrease in mortality in the kidney ischemia/reperfusion model
[65][126], in models of pyelonephritis
[66][156] and neonatal endotoxemia
[67][157], as well as in a murine model of systemic inflammation induced by intravenous injection of TNF
[68][158].
Identification of mitochondria as a phenoptosis checkpoint is also supported by a recent observation that high plasma level of very long omega-3 fatty acids lowered the risk for a fatal outcome in case of COVID-19
[69][159]. Most likely, omega-3 fatty acids prevented the formation of the NLRP3 inflammasome, which was activated in response to SARS-CoV2 and was found to be abundant in various tissues of postmortem patients upon autopsy
[70][160].
In addition, the possible interruption of phenoptotic programs at the recognition stage of PAMPs or DAMPs could be a useful strategy to combat various life-threatening diseases. If so, the phenoptosis execution may be prevented by diminishing the level of certain DAMPs. And indeed, genetic knockouts, neutralizing antibodies, and pharmacological agents that inhibit DAMPs or prevent the activation of DAMP receptors such as TLRs, RAGE, NLRP3 inflammasome, and P2X7 ATP receptor, significantly attenuate the course and reduce mortality in animal models of systemic sterile inflammation
[71][161]. The serum S100A8/A9 and HMGB1 levels were correlated an increased risk of lethal thrombosis
[72][162]. Paquinimod, a specific inhibitor of S100A8/A9, reduced the number of aberrant neutrophils, eliminated lung damage, and protected mice in a lethal model of murine coronavirus infection
[73][75]. Neutralizing antibodies against DAMPs significantly improved animal survival in models of endotoxemia and sepsis
[53][46]. Small molecule inhibitors that prevent the secretion of HMGB1 and serum protein haptoglobin, which binds to extracellular HMGB1, have also been shown to have protective effects
[74][163]. The important role of CIRP has been confirmed by the findings that CIRP−/− knockout mice are resistant to CLP sepsis
[30]. In support of the role of extracellular histones in sepsis, several negatively charged molecules, including heparin, chondroitin sulfate, and high molecular weight hyaluronan, which can bind to histones of NETs were shown to protect against sepsis
[75][164]. P2X receptor blockade or treatment with apyrase, that removes extracellular ATP, protects mice from lethal endotoxemia
[53][46].
One more checkpoint might be on the level of T-cells. Kim et al. who studied the cytokine storm in lymphocyte-depleted mice showed that T cells are necessary and sufficient to temper the overreaction of the innate immune system
[76][77][165,166].