SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small CD45− Precursors of Hematopoietic and Endothelial Cells and in Response to Virus Spike Protein Activates the Nlrp3 Inflammasome

Adamiak

et al. 2020

Stem Cell Rev and Rep

Self Cite

Evidence indicates that bone marrow (BM)-residing hematopoietic stem/progenitor cells (HSPCs) are released into peripheral blood (PB) after administration of pro-mobilizing drugs, which induce a state of sterile inflammation in the BM microenvironment. In the reverse process, as seen after hematopoietic transplantation, intravenously injected HSPCs home and engraft into BM niches. Here again, conditioning for transplantation by myeloablative chemo- or radiotherapy induces a state of sterile inflammation that promotes HSPC seeding to BM stem cell niches. Therefore, the trafficking of HSPCs and their progeny, including granulocytes and monocytes/macrophages, is regulated by a response to pro-inflammatory stimuli. This responsiveness to inflammatory cues is also preserved after malignant transformation of hematopoietic cells. Results from our laboratory indicate that the responsiveness of hematopoietic cells to pro-inflammatory stimuli is orchestrated by Nlrp3 inflammasome. As reported, HO-1 effectively attenuates intracellular activation of Nlrp3 inflammasome as well as the pro-inflammatory effects of several humoral mediators, including complement cascade (ComC) cleavage fragments that promote migration of hematopoietic cells. Based on this finding, inhibition of HO-1 activity may become a practical strategy to enhance the mobilization and homing of normal HSPCs, and, alternatively, its activation may prevent unwanted spread and in vivo expansion of leukemic cells.

Section: Resultsmentioning

confidence: 99%

Heme Oxygenase 1 (HO-1) as an Inhibitor of Trafficking of Normal and Malignant Hematopoietic Stem Cells – Clinical and Translational Implications

Adamiak

et al. 2020

Stem Cell Rev and Rep

Self Cite

“…Interesting novel data supports the evidence of NLRP3 inflammasome activation in response to SARS-CoV-2-S/Angiotensin-converting enzyme-2 receptor binding in hematopoietic and endothelial cells [ 127 ]. In this regard, the role of pyroptosis has not been investigated in detail yet, but one can speculate that the overactivation of NLRP3 inflammasome and the consequent pyroptotic cell death might be one of the contributing factors in severe cases of COVID-19.…”

Section: Cell Death Pathways In Emerging Coronavirusesmentioning

confidence: 87%

Cell death signalling in virus infection

Imre

2020

Cellular Signalling

Apoptosis, necroptosis and pyroptosis represent three major regulated cell death modalities. Apoptosis features cell shrinkage, nuclear fragmentation and cytoplasm-blebbing. Necroptosis and pyroptosis exhibit osmotic imbalances in the cell accompanied by early membrane ruptures, which morphologically resembles necrosis. Importantly, these two lytic cell death forms facilitate the release of damage associated molecular patterns into the extracellular space leading to inflammatory response. Whereas, during apoptosis, the membrane integrity is preserved and the apoptotic cell is removed by neighbouring cells ensuring the avoidance of immune-stimulation. Viruses comprise a versatile group of intracellular pathogens, which elicit various strategies to infect and to propagate. Viruses are recognized by a myriad of pathogen recognition receptors in the human cells, which consequently lead to activation of the immune system and in certain circumstances cell-autonomous cell death. Importantly, the long-standing view that a cell death inducing capacity of a virus is equal to its pathogenic potential seems to be only partially valid. The altruistic cell death of an infected cell may serve the whole organism by ultimately curbing the way of virus manufacturing. In fact, several viruses express “anti-cell death” proteins to avoid this viral-defence mechanism. Conversely, some viruses hijack cell death pathways to selectively destroy cell populations in order to compromise the immune system of the host. This review discusses the pros and cons of virus induced cell death from the perspective of the host cells and attempts to provide a comprehensive overview of the complex network of cell death signalling in virus infection.

“…This inflammatory response, composed of IL-1β and other cytokines, results from assembly/activation of a multiprotein host machinery known as the inflammasome in both immune and non-immune cells such as airway epithelial cells – the most prominent is the NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3)-inflammasome – and several lines of evidence tie activation of the NLRP3-inflammasome to severe SARS-CoV-2 pathology, including i) individuals with comorbidities such as diabetes, atherosclerosis, and obesity (all pro-inflammatory conditions marked by NLRP3 activation) 3–8 are at greater risk for severe disease 9–11 , ii) viroporins expressed by the closely-related SARS-CoV activate the NLRP3 inflammasome 12 , and iii) bats, the asymptomatic reservoir of CoVs that are highly pathogenic in humans, are naturally defective in activating the NLRP3-inflammasome 13 . Although cellular ACE2 engagement by SARS-CoV-2 spike protein can cause expression of pro-inflammatory genes 14 , whether CoV-2 activates the inflammasome remains unexplored.…”

Section: Main Textmentioning

confidence: 99%

SARS-CoV-2 viroporin triggers the NLRP3 inflammatory pathway

Chitre

Akinyemi

et al. 2020

Preprint

Cytokine storm resulting from a heightened inflammatory response is a prominent feature of severe COVID-19 disease. This inflammatory response results from assembly/activation of a cell-intrinsic defense platform known as the inflammasome. We report that the SARS-CoV-2 viroporin encoded by ORF3a activates the NLRP3 inflammasome, the most promiscuous of known inflammasomes. ORF3a triggers IL-1 beta expression via NFkB, thus priming the inflammasome while also activating it via ASC-dependent and -independent modes. ORF3a-mediated inflammasome activation requires efflux of potassium ions and oligomerization between NEK7 and NLRP3. With the selective NLRP3 inhibitor MCC950 able to block ORF3a-mediated inflammasome activation and key ORF3a residues needed for virus release and inflammasome activation conserved in SARS-CoV-2 isolates across continents, ORF3a and NLRP3 present prime targets for intervention.