Intracellular complement (complosome) is expressed in hematopoietic stem/progenitor cells (HSPCs) and regulates cell trafficking, metabolism and proliferation in an intracrine Nlrp3 inflammasome-dependent manner

Ratajczak, Mariusz Z.; Adamiak, Mateusz; Abdelbaset‐Ismail, Ahmed; Bujko, Kamila; Thapa, Arjun; Chumak, Vira; Franczak, Stephanie; Brzeźniakiewicz‐Janus, Katarzyna; Ratajczak, Janina; Kucia, Magdalena

doi:10.1038/s41375-023-01894-0

Cited by 13 publications

(21 citation statements)

References 15 publications

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“…The induction of coagulation is a feature of both normal platelet ExMVs and leukemic ExMvs, as both may express tissue factor. Recent discovery of intracellular complement (complosome) in hematopoietic cells including HSCs raises a question if ExMVs may transfer active complement proteins to other cells [ 69 ]. Moreover, in the case of ExMVs derived from induced pluripotent stem cells (iPS), there is a danger of cargo transfer promoting the neoplastic transformation of target cells [ 70 ].…”

Section: Therapeutic Application Of Exmvs For Drug Delivery In Hemato...mentioning

confidence: 99%

Leukemogenesis occurs in a microenvironment enriched by extracellular microvesicles/exosomes: recent discoveries and questions to be answered

Ratajczak,

Ratajczak

2024

Leukemia

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In single-cell organisms, extracellular microvesicles (ExMVs) were one of the first cell-cell communication platforms that emerged very early during evolution. Multicellular organisms subsequently adapted this mechanism. Evidence indicates that all types of cells secrete these small circular structures surrounded by a lipid membrane that may be encrusted by ligands and receptors interacting with target cells and harboring inside a cargo comprising RNA species, proteins, bioactive lipids, signaling nucleotides, and even entire organelles “hijacked” from the cells of origin. ExMVs are secreted by normal cells and at higher levels by malignant cells, and there are some differences in their cargo. On the one hand, ExMVs secreted from malignant cells interact with cells in the microenvironment, and in return, they are exposed by a “two-way mechanism” to ExMVs secreted by non-leukemic cells. Therefore, leukemogenesis occurs and progresses in ExMVs enriched microenvironments, and this biological fact has pathologic, diagnostic, and therapeutic implications. We are still trying to decipher this intriguing cell-cell communication language better. We will present a current point of view on this topic and review some selected most recent discoveries and papers.

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Section: Therapeutic Application Of Exmvs For Drug Delivery In Hemato...mentioning

confidence: 99%

Leukemogenesis occurs in a microenvironment enriched by extracellular microvesicles/exosomes: recent discoveries and questions to be answered

Ratajczak,

Ratajczak

2024

Leukemia

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“…Moreover, both these pathways operate in a paracrine manner and at the autocrine level in HSPCs [ 8 – 14 ]. Herein, we will discuss data that purinergic signaling and innate immunity carry on their ancient developmental potential in hematopoiesis.…”

Section: Introductionmentioning

confidence: 99%

“…For example, glucose uptake, metabolism rate, and intracellular redox state may activate important intracellular innate immunity pattern recognition receptor—Nlrp3 inflammasome [ 18 ]. This somehow unique receptor is also activated by complement cascade (ComC) cleavage fragments, and, on the other hand, a lack of complement proteins leads to altered metabolism of hematopoietic cells and negatively affects Nlrp3 inflammasome expression [ 14 ]. What is important is that this intracellular innate immunity receptor's expression is regulated by the cells' redox state [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…From several DAMPs released from activated/damaged cells, adenosine triphosphate (ATP) that initiates purinergic signaling is the earliest and most important member [ 23 ]. Recent evidence indicates that both purinergic and ComC signaling operate in a paracrine-dependent manner and are also functional inside cells [ 8 – 14 , 24 ]. This expands our knowledge of the autocrine regulation of hematopoiesis [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…The primary source of complement proteins circulating in PB is the liver; however, recent evidence indicates that complement proteins are expressed in several types of cells in the body [ 11 , 14 , 54 , 55 ]. This intracellular complement, known as “complosome", may regulate several cell functions by engaging cytosol and cell surface-expressed ComC receptors (C3aR, C5aR1, and C5aR2) if activated.…”

Section: Introductionmentioning

confidence: 99%

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Hematopoiesis Revolves Around the Primordial Evolutional Rhythm of Purinergic Signaling and Innate Immunity – A Journey to the Developmental Roots

Ratajczak,

Bujko,

Brzezniakiewicz-Janus

et al. 2024

Stem Cell Rev and Rep

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A cell's most significant existential task is to survive by ensuring proper metabolism, avoiding harmful stimuli, and adapting to changing environments. It explains why early evolutionary primordial signals and pathways remained active and regulate cell and tissue integrity. This requires energy supply and a balanced redox state. To meet these requirements, the universal intracellular energy transporter purine nucleotide-adenosine triphosphate (ATP) became an important signaling molecule and precursor of purinergic signaling after being released into extracellular space. Similarly, ancient proteins involved in intracellular metabolism gave rise to the third protein component (C3) of the complement cascade (ComC), a soluble arm of innate immunity. These pathways induce cytosol reactive oxygen (ROS) and reactive nitrogen species (RNS) that regulate the redox state of the cells. While low levels of ROS and RNS promote cell growth and differentiation, supra-physiological concentrations can lead to cell damage by pyroptosis. This balance explains the impact of purinergic signaling and innate immunity on cell metabolism, organogenesis, and tissue development. Subsequently, along with evolution, new regulatory cues emerge in the form of growth factors, cytokines, chemokines, and bioactive lipids. However, their expression is still modulated by both primordial signaling pathways. This review will focus on the data that purinergic signaling and innate immunity carry on their ancient developmental task in hematopoiesis and specification of hematopoietic stem/progenitor cells (HSPCs). Moreover, recent evidence shows both these regulatory pathways operate in a paracrine manner and inside HSPCs at the autocrine level. Graphical Abstract

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Intracellular complement and immunometabolism: The advantages of compartmentalization

King,

Blom

2024

Eur J Immunol

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The complement system is a proteolytic cascade triggered by pathogen and danger‐associated molecular patterns, with resultant outcomes of inflammation, cellular activation, and opsonization of material for removal by phagocytosis. While first discovered as an activity in serum, it is now recognized that complement components play important roles at local and individual cell‐intrinsic levels. In particular, apart from the extracellular serum activities of complement, it is now believed that complement also acts intracellularly, as part of a cellular signal transduction cascade that can stimulate cellular survival and activation, and individual immune cell phenotypes, via effects on cellular metabolism. This review will describe what is currently known about how complement functions in intracellular signal transduction, and outline the functional advantages of a compartmentalized and intracellular complement system.

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Intracellular complement (complosome) is expressed in hematopoietic stem/progenitor cells (HSPCs) and regulates cell trafficking, metabolism and proliferation in an intracrine Nlrp3 inflammasome-dependent manner

Cited by 13 publications

References 15 publications

Leukemogenesis occurs in a microenvironment enriched by extracellular microvesicles/exosomes: recent discoveries and questions to be answered

Leukemogenesis occurs in a microenvironment enriched by extracellular microvesicles/exosomes: recent discoveries and questions to be answered

Hematopoiesis Revolves Around the Primordial Evolutional Rhythm of Purinergic Signaling and Innate Immunity – A Journey to the Developmental Roots

Intracellular complement and immunometabolism: The advantages of compartmentalization

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