Early studies have shown that erythrocytes have caspase-3 and caspase-8 and are capable of dying through an apoptotic-like cell death triggered by Ca2+ ionophores. This cell death is associated with apoptosis-like morphological signs, including cell shrinkage, membrane blebbing, and phosphatidylserine externalization. To emphasize that mature erythrocytes don't have the apoptotic mitochondrial machinery and distinguish this unique cell death modality from apoptosis, it was named "eryptosis". Over recent decades, our knowledge of eryptosis has been significantly expanded, providing more insights into the uniqueness of cell death pathways in erythrocytes. In this review, we aim to summarize our current understanding of eryptosis, formulate the nomenclature and guidelines to interpret results of eryptosis studies, provide a synopsis of morphological and biochemical features of eryptosis, and highlight the role of eryptosis in health and disease, including its druggability.

• MeSH
• apoptóza MeSH
• eryptóza * účinky léků   fyziologie   MeSH
• erytrocyty * metabolismus   účinky léků   cytologie   MeSH
• lidé MeSH
• terminologie jako téma MeSH
• vápník metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• vápník MeSH

Over the recent years, our understanding of the cell death machinery of mature erythrocytes has been greatly expanded. It resulted in the discovery of several regulated cell death (RCD) pathways in red blood cells. Apoptosis (eryptosis) and necroptosis of erythrocytes share certain features with their counterparts in nucleated cells, but they are also critically different in particular details. In this review article, we summarize the cell death subroutines in the erythroid precursors (apoptosis, necroptosis, and ferroptosis) in comparison to mature erythrocytes (eryptosis and erythronecroptosis) to highlight the consequences of organelle clearance and associated loss of multiple components of the cell death machinery upon erythrocyte maturation. Recent advances in understanding the role of erythrocyte RCDs in health and disease have expanded potential clinical applications of these lethal subroutines, emphasizing their contribution to the development of anemia, microthrombosis, and endothelial dysfunction, as well as their role as diagnostic biomarkers and markers of erythrocyte storage-induced lesions. Fas signaling and the functional caspase-8/caspase-3 system are not indispensable for eryptosis, but might be retained in mature erythrocytes to mediate the crosstalk between both erythrocyte-associated RCDs. The ability of erythrocytes to switch between eryptosis and necroptosis suggests that their cell death is not a simple unregulated mechanical disintegration, but a tightly controlled process. This allows investigation of eventual pharmacological interventions aimed at individual cell death subroutines of erythrocytes.

• Klíčová slova
• Apoptosis, Cell death, Ferroptosis, Necroptosis, Red blood cell,
• MeSH
• apoptóza * MeSH
• buněčná smrt MeSH
• eryptóza MeSH
• erytrocyty * metabolismus   cytologie   MeSH
• ferroptóza MeSH
• lidé MeSH
• nekroptóza MeSH
• signální transdukce * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Necroptosis is considered a programmed necrosis that requires receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and pore-forming mixed lineage kinase domain-like protein (MLKL) to trigger a regulated cell membrane lysis. Membrane rupture in necroptosis has been shown to fuel innate immune response due to release of damage-associated molecular patterns (DAMPs). Recently published studies indicate that mature erythrocytes can undergo necroptosis as well. In this review, we provide an outline of multiple cell death modes occurring in erythrocytes, discuss possible immunological aspects of diverse erythrocyte cell deaths, summarize available evidence related to the ability of erythrocytes to undergo necroptosis, outline key involved molecular mechanisms, and discuss the potential implication of erythrocyte necroptosis in the physiology and pathophysiology. Furthermore, we aim to highlight the interplay between necroptosis and eryptosis signaling in erythrocytes, emphasizing specific characteristics of these pathways distinct from their counterparts in nucleated cells. Thus, our review provides a comprehensive summary of the current knowledge of necroptosis in erythrocytes. To reflect critical differences between necroptosis of nucleated cells and necroptosis of erythrocytes, we suggest a term erythronecroptosis for necroptosis of enucleated cells.

• Klíčová slova
• Eryptosis, Erythrocyte, Erythronecroptosis, MLKL, Necroptosis, RIPK1, Red blood cells, Regulated cell death,
• MeSH
• eryptóza MeSH
• erytrocyty * metabolismus   patologie   MeSH
• lidé MeSH
• nekroptóza * MeSH
• nekróza MeSH
• proteinkinasy metabolismus   MeSH
• serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• MLKL protein, human MeSH Prohlížeč
• proteinkinasy MeSH
• RIPK1 protein, human MeSH Prohlížeč
• RIPK3 protein, human MeSH Prohlížeč
• serin-threoninkinasy interagující s receptory MeSH

Eryptosis is a regulated cell death (RCD) of mature erythrocytes initially described as a counterpart of apoptosis for enucleated cells. However, over the recent years, a growing number of studies have emphasized certain differences between both cell death modalities. In this review paper, we underline the hallmarks of eryptosis and apoptosis and highlight resemblances and dissimilarities between both RCDs. We summarize and critically discuss differences in the impact of caspase-3, Ca2+ signaling, ROS signaling pathways, opposing roles of casein kinase 1α, protein kinase C, Janus kinase 3, cyclin-dependent kinase 4, and AMP-activated protein kinase to highlight a certain degree of divergence between apoptosis and eryptosis. This review emphasizes the crucial importance of further studies that focus on deepening our knowledge of cell death machinery and identifying novel differences between cell death of nucleated and enucleated cells. This might provide evidence that erythrocytes can be defined as viable entities capable of programmed cell destruction. Additionally, the revealed cell type-specific patterns in cell death can facilitate the development of cell death-modulating therapeutic agents.

• Klíčová slova
• Ca2+ signaling, Casein kinase 1α, Caspase-3, Regulated cell death, p38 MAPK,
• MeSH
• apoptóza * MeSH
• buněčná smrt MeSH
• eryptóza * MeSH
• erytrocyty metabolismus   MeSH
• fosfatidylseriny metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• signální transdukce MeSH
• vápník metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• fosfatidylseriny MeSH
• reaktivní formy kyslíku MeSH
• vápník MeSH