Újabb genetikai elemzés erősítette meg, hogy az NLRP3 velünk született immunitást szabályzó fehérje túlaktiválása okozza a covid-19 halálhoz vezető cytokin viharát. (1)
Olyan génváltozat a halálosabb az NLRP3-nál, amely több citokint termel. (2)
Az NLRP3- at, mint ahogy mindenki tudja, aki eddig nem hunyta be a szemét a cofilin deaktíválásán keresztül lehet hatékonyan visszaszabályozni, úgy, hogy ne haljál bele az NLRP3 egyébként jószándékúnak indult tevékenységébe. (3)
A cofilint meg egyszerűen és természetesen is lehet deaktiválni az agyban, ahol a túl aktivált microgliák dühöngenek, csakhogy annak a megemlítése hivatalosan be van tiltva, mert még megtudnák mások is. (4)
As such, this N protein promotes the production of pro-inflammatory cytokines and aggravates acute inflammation and lung injury and, therefore, may hasten death [22]. In the acute respiratory distress syndrome, the cytokine storm in response to SARS-CoV-2 infection rather than viral replication or infection causes death in severe COVID-19 cases [21].
we may hypothesize that the outcome of COVID-19 is aggravated by the presence of T2DM, obesity and hypertension because patients with those conditions show an activated NLRP3 inflammasome which is probably further activated by the infection. These findings extent the results of Lopes-Reyes et al. [37] who reported that SARS-CoV-2 infection may exacerbate pre-existing systemic inflammatory state of obese people by activating the NLRP3 inflammasome and releasing proinflammatory cytokines. These results also explain our findings that the NLPR3 SNVs determined in our study may interact with those comorbid disorders thereby aggravating the outcome of COVID-19
After the age of 55 years, the risk of death due to COVID-19 increases linearly [38]. Such effects may be attributed to the effects of age on the comorbid disorders such as T2DM and hypertension and by the effects of NLRP3 inflammasome-associated inflammaging, which is accompanied by increased inflammatory mediators, AGEs, mitochondrial dysfunctions, reactive oxygen species, genomic instability, hypoxia, etc. [39].
In our study, male sex significantly and indirectly affected COVID-19 outcome by the mediating effects of SSCseverity and increased inflammation. Previously, it was shown that male sex predicts death with an OR=1.46 (95% CI 1.31-1.62) [38]. It is important to note that in male COVID-19 patients overactivation of the NLRP3 inflammasome is accompanied by increased lethality [40]. Higher plasma levels of IL-8 and IL-18 as well as stronger induction of non-classical monocytes are seen in male COVID-19 patients [41]. Testosterone may activate the NLRP3 inflammasome directly or via effects on mitochondrial ROS, while progesterone and estrogen may inhibit the inflammasome [41]
NLRP3 inflammasome activation may contribute to beneficial hostresponses directed against the virus as well as detrimental effects by causing hyperinflammation [9].
As described in the Introduction, SSC has protective effects and is part of the acute phase response and is characterized by fatigue, anergy, lethargy, myalgia, hyperesthesia, psychomotor retardation, loss of libido, anhedonia, and loss of appetite [13]. SSC is induced during the acute phase response by pro-inflammatory cytokines, including IL-6, IL-1β and TNF-α [13,44]. For example, increased IL-1 production causes loss of appetite and other infection-associated SSC symptoms [13,45], supporting the role of the NLRP3 inflammasome. Moreover, headache, which is another SSC symptom, is associated with NLRP3 inflammasome activation and increased IL-6 levels [46].
Increasing age is accompanied by overactivation of the NLRP3 explaining increased lethality due to COVID19 [56], but not the inhibitory effects on SSC.
All in all, it appears that intersections among the NLRP3 rs10754558 genetic variant, increasing age and male sex may increase risk toward critical COVID-19 by attenuating SSC.
1- In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach. (1-3) Michael Maes,
https://www.medrxiv.org/content/10.1101/2021.09.26.21264127v1.full.pdf
2-
he data in study reveals for the first time that patients with the GG genotype of NLRP3 rs10754558 are more prone to CAD and suffer poor prognosis after PCI. Meanwhile, the IL-1β concentrations of subjects carrying G allele of NLRP3 rs10754558 had an obvious increase compared with subjects carrying C allele. These results suggest that the G allele of NLRP3 rs10754558 may be involved in the progression of atherosclerosis in CAD patients and the pathogenicity of the G allele of the NLRP3 rs10754558 was maybe associated with the level of IL-1β in serum.
In conclusion, the present study shows that the G allele of NLRP3 rs10754558 is associated with the occurrence and poor prognosis of CAD in Chinese Han population. The G allele susceptibility to CAD is maybe associated with the increased level of serum IL-1β.
Research Article | Open Access
Volume 2016 |Article ID 3185397 | https://www.hindawi.com/journals/bmri/2016/3185397/
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The NLRP3 rs10754558 Polymorphism Is Associated with the Occurrence and Prognosis of Coronary Artery Disease in the Chinese Han Population
Dong Zhou,
3- Park YH, Kastner D, Chae JJ. Cofilin-1 is an essential redox sensor for NLRP3 inflammasome activation. Pediatr Rheumatol Online J. 2015;13(Suppl 1):O52. Published 2015 Sep 28. doi:10.1186/1546-0096-13-S1-O52
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597601/
4- Aleksic, M., Walcher, D., Giehl, K. et al. Signalling processes involved in C-peptide-induced chemotaxis of CD4-positive lymphocytes. Cell. Mol. Life Sci. 66, 1974–1984 (2009). https://link.springer.com/article/10.1007/s00018-009-9057-y
https://link.springer.com/art…/10.1007%2Fs00018-009-9057-y
