scholarly journals Cell Death and Inflammation: The Role of Mitochondria in Health and Disease

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 537
Author(s):  
Anna Picca ◽  
Riccardo Calvani ◽  
Hélio José Coelho-Junior ◽  
Emanuele Marzetti
Keyword(s):  
Cell Death ◽  
Mitochondrial Dynamics ◽  
Cpg Islands ◽  
Innate Immune ◽  
Low Grade ◽  
Interferon Production ◽  
Cellular Processes ◽  
Molecular Pattern ◽  
Extracellular Compartment ◽  
Dying Cells

Mitochondria serve as a hub for a multitude of vital cellular processes. To ensure an efficient deployment of mitochondrial tasks, organelle homeostasis needs to be preserved. Mitochondrial quality control (MQC) mechanisms (i.e., mitochondrial dynamics, biogenesis, proteostasis, and autophagy) are in place to safeguard organelle integrity and functionality. Defective MQC has been reported in several conditions characterized by chronic low-grade inflammation. In this context, the displacement of mitochondrial components, including mitochondrial DNA (mtDNA), into the extracellular compartment is a possible factor eliciting an innate immune response. The presence of bacterial-like CpG islands in mtDNA makes this molecule recognized as a damaged-associated molecular pattern by the innate immune system. Following cell death-triggering stressors, mtDNA can be released from the cell and ignite inflammation via several pathways. Crosstalk between autophagy and apoptosis has emerged as a pivotal factor for the regulation of mtDNA release, cell's fate, and inflammation. The repression of mtDNA-mediated interferon production, a powerful driver of immunological cell death, is also regulated by autophagy-apoptosis crosstalk. Interferon production during mtDNA-mediated inflammation may be exploited for the elimination of dying cells and their conversion into elements driving anti-tumor immunity.

scholarly journals STING SNP R293Q Is Associated with a Decreased Risk of Aging-Related Diseases

Gerontology ◽  
2018 ◽  
Vol 65 (2) ◽  
pp. 145-154 ◽  
Author(s):  
Lutz Hamann ◽  
Juan S. Ruiz-Moreno ◽  
Malgorzata Szwed ◽  
Malgorzata Mossakowska ◽  
Linn Lundvall ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Bacterial Infections ◽  
Healthy Aging ◽  
The Elderly ◽  
Innate Immune ◽  
Low Grade ◽  
Associated Diseases ◽  
Chronic Lung Diseases ◽  
Sting Pathway

Background: Aging is a multifactorial process driven by several conditions. Among them, inflamm-aging is characterized by chronic low-grade inflammation driving aging-related diseases. The aged immune system is characterized by the senescence-associated secretory phenotype, resulting in the release of proinflammatory cytokines contributing to inflamm-aging. Another possible mechanism resulting in inflamm-aging could be the increased release of danger- associated molecular patterns (DAMPs) by increased cell death in the elderly, leading to a chronic low-grade inflammatory response. Several pattern recognition receptors of the innate immune system are involved in recognition of DAMPs. The DNA-sensing cGAS-STING pathway plays a pivotal role in combating viral and bacterial infections and recognizes DNA released by cell death during the process of aging, which in turn may result in increased inflamm-aging. Objective: The aim of this study was to investigate whether a variation within the STING gene with known impaired function may be associated with protection from aging-related diseases by decreasing the process of inflamm-aging. Methods: STING (Tmem173) R293Q was genotyped in a cohort of 3,397 aged subjects (65–103 years). The distribution of the variant allele in healthy subjects and subjects suffering from aging-associated diseases was compared by logistic regression analysis. Results: We show here that STING 293Q allele carriers were protected from aging-associated diseases (OR = 0.823, p = 0.038). This effect was much stronger in the subgroup of subjects suffering from chronic lung diseases (OR = 0.730, p = 0.009). Conclusion: Our results indicate that decreased sensitivity of the innate immune receptors is associated with healthy aging, most likely due to a decreased process of inflamm-aging.

scholarly journals Mitochondrial DNA: A Key Regulator of Anti-Microbial Innate Immunity

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 86 ◽  
Author(s):  
Saima Kausar ◽  
Liqun Yang ◽  
Muhammad Nadeem Abbas ◽  
Xin Hu ◽  
Yongju Zhao ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mitochondrial Dna ◽  
Signaling Pathways ◽  
Inflammatory Diseases ◽  
Cpg Islands ◽  
Innate Immune ◽  
Cellular Damage ◽  
Immune Signaling ◽  
Molecular Pattern ◽  
Characteristic Features

During the last few years, mitochondrial DNA has attained much attention as a modulator of immune responses. Due to common evolutionary origin, mitochondrial DNA shares various characteristic features with DNA of bacteria, as it consists of a remarkable number of unmethylated DNA as 2′-deoxyribose cytidine-phosphate-guanosine (CpG) islands. Due to this particular feature, mitochondrial DNA seems to be recognized as a pathogen-associated molecular pattern by the innate immune system. Under the normal physiological situation, mitochondrial DNA is enclosed in the double membrane structure of mitochondria. However, upon pathological conditions, it is usually released into the cytoplasm. Growing evidence suggests that this cytosolic mitochondrial DNA induces various innate immune signaling pathways involving NLRP3, toll-like receptor 9, and stimulator of interferon genes (STING) signaling, which participate in triggering downstream cascade and stimulating to produce effector molecules. Mitochondrial DNA is responsible for inflammatory diseases after stress and cellular damage. In addition, it is also involved in the anti-viral and anti-bacterial innate immunity. Thus, instead of entire mitochondrial importance in cellular metabolism and energy production, mitochondrial DNA seems to be essential in triggering innate anti-microbial immunity. Here, we describe existing knowledge on the involvement of mitochondrial DNA in the anti-microbial immunity by modulating the various immune signaling pathways.

scholarly journals Proteomic Analysis of Low-Grade, Early-Stage Endometrial Carcinoma Reveals New Dysregulated Pathways Associated with Cell Death and Cell Signaling

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 794
Author(s):  
Álvaro López-Janeiro ◽  
Ignacio Ruz-Caracuel ◽  
Jorge L. Ramón-Patino ◽  
Vivian De Los Ríos ◽  
María Villalba Esparza ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Cell Signaling ◽  
Endometrial Carcinoma ◽  
Proteomic Analysis ◽  
Early Stage ◽  
Innate Immune ◽  
Future Research ◽  
Low Grade

Low-grade, early-stage endometrial carcinoma (EC) is the most frequent malignant tumor of the uterine corpus. However, the molecular alterations that underlie these tumors are far from being fully understood. The purpose of this study is to describe dysregulated molecular pathways from EC patients. Sixteen samples of tumor tissue and paired healthy controls were collected and both were subjected to mass spectrometry (MS)/MS proteomic analysis. Gene ontology and pathway analysis was performed to discover dysregulated pathways and/or proteins using different databases and bioinformatic tools. Dysregulated pathways were cross-validated in an independent external cohort. Cell signaling, immune response, and cell death-associated pathways were robustly identified. The SLIT/ROBO signaling pathway demonstrated dysregulation at the proteomic and transcriptomic level. Necroptosis and ferroptosis were cell death-associated processes aberrantly regulated, in addition to apoptosis. Immune response-associated pathways showed a dominance of innate immune responses. Tumor immune infiltrates measured by immunofluorescence demonstrated diverse lymphoid and myeloid populations. Our results suggest a role of SLIT/ROBO, necroptosis, and ferroptosis, as well as a prominent role of innate immune response in low-grade, early-stage EC. These results could guide future research in this group of tumors.

scholarly journals Mitochondrial Modulations, Autophagy Pathways Shifts in Viral Infections: Consequences of COVID-19

2021 ◽  
Vol 22 (15) ◽  
pp. 8180
Author(s):  
Shailendra Pratap Singh ◽  
Salomon Amar ◽  
Pinky Gehlot ◽  
Sanjib K. Patra ◽  
Navjot Kanwar ◽  
...  
Keyword(s):  
Cell Death ◽  
Essential Role ◽  
Viral Infections ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Innate Immune ◽  
Innate Immune Signaling ◽  
Promising Target ◽  
Intracellular Organelles ◽  
Viral Proliferation

Mitochondria are vital intracellular organelles that play an important role in regulating various intracellular events such as metabolism, bioenergetics, cell death (apoptosis), and innate immune signaling. Mitochondrial fission, fusion, and membrane potential play a central role in maintaining mitochondrial dynamics and the overall shape of mitochondria. Viruses change the dynamics of the mitochondria by altering the mitochondrial processes/functions, such as autophagy, mitophagy, and enzymes involved in metabolism. In addition, viruses decrease the supply of energy to the mitochondria in the form of ATP, causing viruses to create cellular stress by generating ROS in mitochondria to instigate viral proliferation, a process which causes both intra- and extra-mitochondrial damage. SARS-COV2 propagates through altering or changing various pathways, such as autophagy, UPR stress, MPTP and NLRP3 inflammasome. Thus, these pathways act as potential targets for viruses to facilitate their proliferation. Autophagy plays an essential role in SARS-COV2-mediated COVID-19 and modulates autophagy by using various drugs that act on potential targets of the virus to inhibit and treat viral infection. Modulated autophagy inhibits coronavirus replication; thus, it becomes a promising target for anti-coronaviral therapy. This review gives immense knowledge about the infections, mitochondrial modulations, and therapeutic targets of viruses.

Review: Soluble innate immune pattern-recognition proteins for clearing dying cells and cellular components: implications on exacerbating or resolving inflammation

2010 ◽  
Vol 16 (3) ◽  
pp. 191-200 ◽  
Author(s):  
Michael L. Litvack ◽  
Nades Palaniyar
Keyword(s):  
Pattern Recognition ◽  
Cell Death ◽  
Treatment Strategies ◽  
Innate Immune ◽  
Live Cells ◽  
Death Process ◽  
Clear Understanding ◽  
Phagocytic Cells ◽  
Molecular Patterns ◽  
Dying Cells

Soluble innate immune pattern-recognition proteins (sPRPs) identify non-self or altered-self molecular patterns. Dying cells often display altered-self arrays of molecules on their surfaces. Hence, sPRPs are ideal for recognizing these cells and their components. Dying cell surfaces often contain, or allow the access to different lipids, intracellular glycoproteins and nucleic acids such as DNA at different stages of cell death. These are considered as ‘eat me’ signals that replace the native ‘don’t eat me’ signals such as CD31, CD47 present on the live cells. A programmed cell death process such as apoptosis also generates cell surface blebs that contain intracellular components. These blebs are easily released for effective clearance or signalling. During late stages of cell death, soluble components are also released that act as ‘find me’ signal (e.g. LysoPC, nucleotides). The sPRPs such as collectins, ficolins, pentraxins, sCD14, MFG-E8, natural IgM and C1q can effectively identify some of these specific molecular patterns. The biological end-point is different depending on sPRP, tissue, stage of apoptosis and the type of cell death. The sPRPs that reside in the immune-privileged surfaces such as lungs often act as opsonins and enhance a silent clearance of dying cells and cellular material by macrophages and other phagocytic cells. Although the recognition of these materials by complement-activating proteins could amplify the opsonic signal, this pathway may aggravate inflammation. Clear understanding of the involvement of specific sPRPs in cell death and subsequent clearance of dying cell and their components is essential for devising appropriate treatment strategies for diseases involving infection, inflammation and auto-antibody generation.

scholarly journals Efferocytosis: An Interface between Apoptosis and Pathophysiology

2021 ◽  
Author(s):  
Bichandarkoil Jayaram Pratima ◽  
Namasivayam Nalini
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
Immune System ◽  
Large Family ◽  
Pathogen Invasion ◽  
Molecular Pattern ◽  
Cellular Debris ◽  
Established Cell ◽  
Dying Cells ◽  
Shed Light

Several cell death modes, each with a unique feature and mode of inducing cell death have been established. Cell death occurring under physiological conditions is primarily caused by apoptosis, which is a non-inflammatory or silent process, whereas necroptosis or pyroptosis is triggered by pathogen invasion, which stimulates the immune system and induces inflammation. In physiology, clearing dead cells and associated cellular debris is necessary since billions of cells die during mammalian embryogenesis and every day in adult organisms. For degradation, dead cells produced by apoptosis are quickly engulfed by macrophages. This chapter will present a description of the phagocytosis of dead and dying cells, by a process known as efferocytosis. Macrophages and, to a lesser degree, other ‘professional’ phagocytes (such as monocytes and dendritic cells) and ‘non-professional’ phagocytes, such as epithelial cells, conduct efferocytosis. Recent discoveries have shed light on this mechanism and how it works to preserve homeostasis of tissue, repair of tissue and health of the organism. Caspases are a large family of proteases of cysteine acting in cascades. A cascade leading to activation of caspase 3 mediates apoptosis and is responsible for killing cells, hiring macrophages, and presenting a “eat me” signal(s). If macrophages do not effectively engulf apoptotic cells, they undergo secondary necrosis and release intracellular materials that reflect a molecular pattern associated with injury, which can lead to autoimmune diseases. Here, the processes of efferocytosis are illustrated and the pathophysiological effects that which occur when this phase is abrogated are highlighted.

scholarly journals The P2X7 Receptor in Tumor Immunity

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabio Grassi ◽  
Benedetta De Ponte Conti
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
T Cell ◽  
P2x7 Receptor ◽  
Tissue Repair ◽  
Innate Immune ◽  
Tumor Control ◽  
Extracellular Adenosine ◽  
Molecular Pattern ◽  
Cell Immunity

Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.

scholarly journals Current Understanding of the Mechanisms for Clearance of Apoptotic Cells—A Fine Balance

2013 ◽  
Vol 6 ◽  
pp. JCD.S11037 ◽  
Author(s):  
Lois A. Hawkins ◽  
Andrew Devitt
Keyword(s):  
Cell Death ◽  
Innate Immune System ◽  
Inflammatory Process ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Apoptotic Cells ◽  
Viable Cells ◽  
Effective Removal ◽  
Multicellular Organisms ◽  
Dying Cells

Apoptosis is an important cell death mechanism by which multicellular organisms remove unwanted cells. It culminates in a rapid, controlled removal of cell corpses by neighboring or recruited viable cells. Whilst many of the molecular mechanisms that mediate corpse clearance are components of the innate immune system, clearance of apoptotic cells is an anti-inflammatory process. Control of cell death is dependent on competing pro-apoptotic and anti-apoptotic signals. Evidence now suggests a similar balance of competing signals is central to the effective removal of cells, through so called ‘eat me’ and ‘don't eat me’ signals. Competing signals are also important for the controlled recruitment of phagocytes to sites of cell death. Consequently recruitment of phagocytes to and from sites of cell death can underlie the resolution or inappropriate propagation of cell death and inflammation. This article highlights our understanding of mechanisms mediating clearance of dying cells and discusses those mechanisms controlling phagocyte migration and how inappropriate control may promote important pathologies.

scholarly journals Viral Infection Modulates Mitochondrial Function

2021 ◽  
Vol 22 (8) ◽  
pp. 4260
Author(s):  
Xiaowen Li ◽  
Keke Wu ◽  
Sen Zeng ◽  
Feifan Zhao ◽  
Jindai Fan ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Viral Infection ◽  
Viral Infections ◽  
Mitochondrial Dynamics ◽  
Innate Immune ◽  
Host Cells ◽  
Mitochondrial Morphology ◽  
And Function ◽  
Antiviral Role

Mitochondria are important organelles involved in metabolism and programmed cell death in eukaryotic cells. In addition, mitochondria are also closely related to the innate immunity of host cells against viruses. The abnormality of mitochondrial morphology and function might lead to a variety of diseases. A large number of studies have found that a variety of viral infections could change mitochondrial dynamics, mediate mitochondria-induced cell death, and alter the mitochondrial metabolic status and cellular innate immune response to maintain intracellular survival. Meanwhile, mitochondria can also play an antiviral role during viral infection, thereby protecting the host. Therefore, mitochondria play an important role in the interaction between the host and the virus. Herein, we summarize how viral infections affect microbial pathogenesis by altering mitochondrial morphology and function and how viruses escape the host immune response.

vitreal cells and specialized phagocytes in the chick embryo retina: A TEM and SEM study

1990 ◽  
Vol 48 (3) ◽  
pp. 330-331
Author(s):  
M.A. Cuadros ◽  
M.J. Martinez-Guerrero ◽  
A. Rios
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Acid Phosphatase ◽  
Chick Embryo ◽  
Basement Membrane ◽  
Sem Images ◽  
Intimate Contact ◽  
Cellular Processes ◽  
Sem Study ◽  
Free Cells

In the chick embryo retina (days 3-4 of incubation), coinciding with an increase in cell death, specialized phagocytes characterized by intense acid phosphatase activity have been described. In these preparations, all free cells in the vitreal humor (vitreal cells) were strongly labeled. Conventional TEM and SEM techniques were used to characterize them and attempt to determine their relationship with retinal phagocytes.Two types of vitreal cells were distinguished. The first are located at some distance from the basement membrane of the neuroepithelium, and are rounded, with numerous vacuoles and thin cytoplasmic prolongations. Images of exo- and or endocytosis were frequent; the cells showed a well-developed Golgi apparatus (Fig. 1) In SEM images, the cells was covered with short cellular processes (Fig. 3). Cells lying parallel to or alongside the basement membrane are elongated. The plasma membrane is frequently in intimate contact with the basement membrane. These cells have generally a large cytoplasmic expansion (Fig. 5).

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