Jurnal Internasional BID-ding pada necroptosis di MDS

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Jurnal Internasional BID-ding pada necroptosis di MDS

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In this edition of Wagner and colleagues implicated Rip1 kinase (Ripk1) – necroptosis mediated in myelodysplastic syndrome (MDS) – similar to disease in mice and detecting increased expression of RIPK1 and pseudokinase (MLKL) mixed linease kinase domainases in human MDS samples. 1

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When apoptosis is disabled, mice develop MDS-like diseases, characterized by increased Ripk1 expression and MLKL activation, a feature also observed in a subset of human MDS samples. HSC, hematopoietic stem cells; IFN, interferon; IL-1β, interleukin-1β.

Cell death and signs of inflammatory genes have long been associated with haematological abnormalities of MDS, characterized by abnormal differentiation, mature blood cell deficiency, and predisposing to leukemia. Increased cell death in MDS has been associated with apoptosis; However, many methods of cell death fail to distinguish between apoptosis and other forms of inflammatory cell death such as necroptosis and pyroptosis. While apoptosis is considered immunologically silent, necroptosis and piroptosis cause membrane permeabilization and / or activation of cation channels and release of damage-related molecular patterns (DAMP). DAMP is recognized by pattern recognition receptors (PRR), and they stimulate the production of cytokines and chemokines, thereby inducing a feed-forward cycle of cell death and cell inflammation. DAMPs are like group 1 high mobility boxes (HMGB1) and alarms S100A8 and S100A9 are found to be excessive in plasma MDS 2 where they bind to receptors such as Toll 4 (TLR4) and other receptors to activate NF-κB and promote inflammation . In most cell types, necroptosis requires MLl and kinase activity from Ripk1 and Ripk3. This form of inflammatory cell death can be activated in the downstream of the death receptor (FAS tumor necrosis factor, apoptotic-inducing ligand related to TNF 1945 1945)), PRR such as TLR3 and TLR4, and type I or II interferon receptors. Serine / threonine kinase Ripk1 is a critical mediator of TNF signaling, which determines whether living cells, apoptosis, or necroptosis ensues.

Wagner et al. Showed that mice lacking members of the Bax and Bak proclopotic Bcl-2 family and BH3- only family members Bid (designated triple knockout [TKO]) that develops features such as MDS, including abnormal differentiation in the bone marrow, cytopenia, and the development of leukemia. The Lin Sca1 + c-Kit + population increased and cycled in TKO rats, while myeloid ancestors declined. In the absence of apoptotic signals provided by Bak and Bax in multiple KO mice, Bid seems to coordinate caspase-8-dependent Ripk1 (and Ripk3) cleavage, thereby inhibiting necroptosis. After the loss of Bids on TKO, Ripk1 and Ripk3 mice were protected from cleavage by caspase-8. This resulted in increased levels of Ripk1 and Ripk3, phosphorylation and oligomerization, and the emergence of cells with necrotic morphology in the TKO rat bone marrow, suggesting that necroptosis underlies the loss of progenitor cells (see figure) and bone marrow failure in these mice. . Necroptosis deregulated in rat hematopoietic cells induces systemic inflammation and depletes rat cell and hematopoietic progenitor cells resulting in bone marrow failure. Inhibition of necroptosis or inflammatory signals in this mouse model restores hematopoiesis and significantly delay bone marrow failure. 3 4

To show that Ripk1 mediates the loss of progenitor cells and bone marrow failure in TKO mice. , the authors reduced the Ripk1 level by removing one Ripk1 19459011 allele, but they observed no significant change in the number, or proliferation status of hematopoietic ancestors. However, reducing Ripk1 expression is sufficient to restore red blood cell count and hematocrit and reduce the expression of IL-1β and TNF-α in the bone marrow. Although these data indicate that necroptosis can be responsible, an increase in cytokine / chemokine expression may reflect necroptotic independent functions of Ripk1 or MLL. The kinase activity of Ripk1 can affect cytokine and chemokine transcripts, 5 and Ripk1, Ripk3, and MLK can activate nucleotide binding domains and repeated leucine-rich repeat domains containing 3 (NLRP3) inflammation to produce IL-1β and IL -18 and / or stimulate pyroptosis. 6 7 Consistent with this idea, activation of NLRP3 inflammation and pyroptosis has been observed in MDS patients and mouse models. 8 To definitively show that necroptosis drives the pathogenesis of MDS it will require a genetic and pharmacological approach in several MDS mouse models and patient samples. Ripk1 expression inactivated kinase and analysis of MDS mouse models on Ripk3- and Mlkl-deficient backgrounds will provide genetic evidence for further involvement of necroptosis in MDS. Likewise, the MDS human study focuses on the effects of RIPK1 kinase or MLKL inhibitors in testing in vitro and in vivo colony formation in xenografts that are inherited by MDS patients should explain the pathway of inflammatory cell death and mechanisms acting on human MDS.

Consistent with mouse data they, Wagner et al. detected an increase in the expression of RIPK1 and fosfo-MLKL in a small number of human MDS samples in all disease subtypes. Previous history of infection or autoimmune disease increases the risk of MDS. 9 Thus, infection or immune deregulation can induce proinflammatory cytokines such as TNF which, under conditions of caspase-8 inhibition, are licensed cells to undergo necroptosis. Whether piroptosis and / or necroptosis is used will likely reflect specific cell types in the MDS bone marrow and the nature of the genetic mutations that make up the MDS clone. If activation of the necroptosis pathway persists in larger studies in MDS patients, fosfo-MLK reactivity can function as a biomarker that is useful for this disease and has the potential for other congenital disorders that can cause MDS. Perhaps most importantly, it is possible that RIPK1 kinase inhibitors, which are well tolerated in humans, 10 can provide clinical benefits for MDS patients.

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