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Immunological Investigations Oct 2020Phosphatidylserine (PS) is a naturally occurring anionic phospholipid that is primarily located in the inner leaflet of eukaryotic cell membranes. The role of PS during... (Review)
Review
Phosphatidylserine (PS) is a naturally occurring anionic phospholipid that is primarily located in the inner leaflet of eukaryotic cell membranes. The role of PS during apoptosis is one of the most studied biological functions of PS. Externalization of PS during apoptosis mediates an "eat me" signal for phagocytic uptake, leading to clearance of apoptotic cells and thus maintain self-tolerance by immunological ignorance. However, an emerging view is that PS exposure-mediated cellular uptake is not an immunologically silent event, but rather promoting an active tolerance towards self and foreign proteins. This biological property of PS has been exploited by parasites and viruses in order to evade immune surveillance of the host immune system. Further, this novel immune regulatory property of PS that results in tolerance induction can be harnessed for clinical applications, such as to treat autoimmune conditions and to reduce immunogenicity of therapeutic proteins. This review attempts to provide an overview of the biological functions of PS in the immune response and its potential therapeutic applications.
Topics: Animals; Apoptosis; Drug Design; Drug Development; Humans; Immunotherapy; Molecular Structure; Nanoparticles; Phagocytes; Phagocytosis; Phosphatidylserines; Theranostic Nanomedicine
PubMed: 32204629
DOI: 10.1080/08820139.2020.1738456 -
Immunological Reviews May 2017Apoptosis is an important component of normal tissue physiology, and the prompt removal of apoptotic cells is equally essential to avoid the undesirable consequences of... (Review)
Review
Apoptosis is an important component of normal tissue physiology, and the prompt removal of apoptotic cells is equally essential to avoid the undesirable consequences of their accumulation and disintegration. Professional phagocytes are highly specialized for engulfing apoptotic cells. The recent ability to track cells that have undergone apoptosis in situ has revealed a division of labor among the tissue resident phagocytes that sample them. Macrophages are uniquely programmed to process internalized apoptotic cell-derived fatty acids, cholesterol and nucleotides, as a reflection of their dominant role in clearing the bulk of apoptotic cells. Dendritic cells carry apoptotic cells to lymph nodes where they signal the emergence and expansion of highly suppressive regulatory CD4 T cells. A broad suppression of inflammation is executed through distinct phagocyte-specific mechanisms. A clever induction of negative regulatory nodes is notable in dendritic cells serving to simultaneously shut down multiple pathways of inflammation. Several of the genes and pathways modulated in phagocytes in response to apoptotic cells have been linked to chronic inflammatory and autoimmune diseases such as atherosclerosis, inflammatory bowel disease and systemic lupus erythematosus. Our collective understanding of old and new phagocyte functions after apoptotic cell phagocytosis demonstrates the enormity of ways to mediate immune suppression and enforce tissue homeostasis.
Topics: Animals; Apoptosis; Atherosclerosis; Cholesterol; Dendritic Cells; Fatty Acids; Homeostasis; Humans; Immune Tolerance; Inflammatory Bowel Diseases; Lupus Erythematosus, Systemic; Nucleotides; Phagocytes; Phagocytosis
PubMed: 28462530
DOI: 10.1111/imr.12537 -
Microbial Phagocytic Receptors and Their Potential Involvement in Cytokine Induction in Macrophages.Frontiers in Immunology 2021Phagocytosis is an essential process for the uptake of large (>0.5 µm) particulate matter including microbes and dying cells. Specialized cells in the body perform... (Review)
Review
Phagocytosis is an essential process for the uptake of large (>0.5 µm) particulate matter including microbes and dying cells. Specialized cells in the body perform phagocytosis which is enabled by cell surface receptors that recognize and bind target cells. Professional phagocytes play a prominent role in innate immunity and include macrophages, neutrophils and dendritic cells. These cells display a repertoire of phagocytic receptors that engage the target cells directly, or indirectly opsonins, to mediate binding and internalization of the target into a phagosome. Phagosome maturation then proceeds to cause destruction and recycling of the phagosome contents. Key subsequent events include antigen presentation and cytokine production to alert and recruit cells involved in the adaptive immune response. Bridging the innate and adaptive immunity, macrophages secrete a broad selection of inflammatory mediators to orchestrate the type and magnitude of an inflammatory response. This review will focus on cytokines produced by NF-κB signaling which is activated by extracellular ligands and serves a master regulator of the inflammatory response to microbes. Macrophages secrete pro-inflammatory cytokines including TNFα, IL1β, IL6, IL8 and IL12 which together increases vascular permeability and promotes recruitment of other immune cells. The major anti-inflammatory cytokines produced by macrophages include IL10 and TGFβ which act to suppress inflammatory gene expression in macrophages and other immune cells. Typically, macrophage cytokines are synthesized, trafficked intracellularly and released in response to activation of pattern recognition receptors (PRRs) or inflammasomes. Direct evidence linking the event of phagocytosis to cytokine production in macrophages is lacking. This review will focus on cytokine output after engagement of macrophage phagocytic receptors by particulate microbial targets. Microbial receptors include the PRRs: Toll-like receptors (TLRs), scavenger receptors (SRs), C-type lectin and the opsonic receptors. Our current understanding of how macrophage receptor stimulation impacts cytokine production is largely based on work utilizing soluble ligands that are destined for endocytosis. We will instead focus this review on research examining receptor ligation during uptake of particulate microbes and how this complex internalization process may influence inflammatory cytokine production in macrophages.
Topics: Animals; Antigens, Bacterial; Cytokines; Humans; Immunity, Innate; Macrophages; Mice; NF-kappa B p50 Subunit; Phagocytes; Phagocytosis; Phagosomes; Signal Transduction; Toll-Like Receptors
PubMed: 33995386
DOI: 10.3389/fimmu.2021.662063 -
Seminars in Immunology Apr 2018Apparent redundancy is a recurrent theme in innate immunity in various domains including inflammatory cytokines, chemokines and pattern recognition receptors. While... (Review)
Review
Apparent redundancy is a recurrent theme in innate immunity in various domains including inflammatory cytokines, chemokines and pattern recognition receptors. While sharing core function, different mediators may subserve distinct functions related for instance to production and release (e.g. IL-1α versus IL-1β), predominantly local versus systemic function (e.g. PTX3 versus C-reactive protein) or fine tuning of innate and adaptive responses (chemokines). Based on hard-wired phagocyte recruitment and regulation by a wide spectrum of chemokines and conventional or atypical receptors, I argue that trafficking of phagocytic cells is a robust output of the chemokine system, resistant to genetic or environmental variation. In general, I speculate that the apparent overlap and redundancy observed in core functions represents an evolutionary strategy to preserve robust essential core outputs in the face of genetically or environmentally caused variation.
Topics: Adaptive Immunity; Animals; Biological Evolution; Cell Movement; Chemokines; Cytokines; Humans; Immunity, Innate; Inflammation; Phagocytes; Polymorphism, Genetic; Receptors, Pattern Recognition
PubMed: 29273304
DOI: 10.1016/j.smim.2017.12.006 -
Frontiers in Immunology 2021The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of... (Review)
Review
The rapid and efficient phagocytic clearance of apoptotic cells, termed efferocytosis, is a critical mechanism in the maintenance of tissue homeostasis. Removal of apoptotic cells through efferocytosis prevents secondary necrosis and the resultant inflammation caused by the release of intracellular contents. The importance of efferocytosis in homeostasis is underscored by the large number of inflammatory and autoimmune disorders, including atherosclerosis and systemic lupus erythematosus, that are characterized by defective apoptotic cell clearance. Although mechanistically similar to the phagocytic clearance of pathogens, efferocytosis differs from phagocytosis in that it is immunologically silent and induces a tissue repair response. Efferocytes face unique challenges resulting from the internalization of apoptotic cells, including degradation of the apoptotic cell, dealing with the extra metabolic load imposed by the processing of apoptotic cell contents, and the coordination of an anti-inflammatory, pro-tissue repair response. This review will discuss recent advances in our understanding of the cellular response to apoptotic cell uptake, including trafficking of apoptotic cell cargo and antigen presentation, signaling and transcriptional events initiated by efferocytosis, the coordination of an anti-inflammatory response and tissue repair, unique cellular metabolic responses and the role of efferocytosis in host defense. A better understanding of how efferocytic cells respond to apoptotic cell uptake will be critical in unraveling the complex connections between apoptotic cell removal and inflammation resolution and maintenance of tissue homeostasis.
Topics: Antigen Presentation; Apoptosis; Gene Expression Regulation; Homeostasis; Humans; Inflammation; Phagocytes; Phagocytosis; Phagosomes; Signal Transduction
PubMed: 33959122
DOI: 10.3389/fimmu.2021.631714 -
Cell Host & Microbe May 2023Treating and preventing infections by antimicrobial-resistant bacterial pathogens is a worldwide problem. Pathogens such as Staphylococcus aureus produce an array of...
Treating and preventing infections by antimicrobial-resistant bacterial pathogens is a worldwide problem. Pathogens such as Staphylococcus aureus produce an array of virulence determinants, making it difficult to identify single targets for the development of vaccines or monoclonal therapies. We described a human-derived anti-S. aureus monoclonal antibody (mAb)-centyrin fusion protein ("mAbtyrin") that simultaneously targets multiple bacterial adhesins, resists proteolysis by bacterial protease GluV8, avoids Fc engagement by S. aureus IgG-binding proteins SpA and Sbi, and neutralizes pore-forming leukocidins via fusion with anti-toxin centyrins, while maintaining Fc- and complement-mediated functions. Compared with the parental mAb, mAbtyrin protected human phagocytes and boosted phagocyte-mediated killing. The mAbtyrin also reduced pathology, reduced bacterial burden, and protected from different types of infections in preclinical animal models. Finally, mAbtyrin synergized with vancomycin, enhancing pathogen clearance in an animal model of bacteremia. Altogether, these data establish the potential of multivalent mAbs for treating and preventing S. aureus diseases.
Topics: Animals; Humans; Staphylococcus aureus; Staphylococcal Infections; Antibodies, Monoclonal; Phagocytes; Leukocidins; Methicillin-Resistant Staphylococcus aureus
PubMed: 37098341
DOI: 10.1016/j.chom.2023.04.004 -
Frontiers in Cellular and Infection... 2020The fungal pathogen can cause life-threatening infections in immune compromised individuals. This pathogen is typically acquired via inhalation, and enters the... (Review)
Review
The fungal pathogen can cause life-threatening infections in immune compromised individuals. This pathogen is typically acquired via inhalation, and enters the respiratory tract. Innate immune cells such as macrophages and dendritic cells (DCs) are the first host cells that encounter , and the interactions between and innate immune cells play a critical role in the progression of disease. possesses several virulence factors and evasion strategies to prevent its killing and destruction by pulmonary phagocytes, but these phagocytic cells can also contribute to anti-cryptococcal responses. This review will focus on the interactions between and primary macrophages and dendritic cells (DCs), dealing specifically with the cryptococcal/pulmonary cell interface.
Topics: Cryptococcosis; Cryptococcus neoformans; Dendritic Cells; Humans; Macrophages; Macrophages, Alveolar
PubMed: 32117810
DOI: 10.3389/fcimb.2020.00037 -
Cellular and Molecular Life Sciences :... Jun 2015Over the past two decades, fungal infections have emerged as significant causes of morbidity and mortality in patients with hematological malignancies, hematopoietic... (Review)
Review
Over the past two decades, fungal infections have emerged as significant causes of morbidity and mortality in patients with hematological malignancies, hematopoietic stem cell or solid organ transplantation and acquired immunodeficiency syndrome. Besides neutrophils and CD4(+) T lymphocytes, which have long been known to play an indispensable role in promoting protective antifungal immunity, mononuclear phagocytes are now being increasingly recognized as critical mediators of host defense against fungi. Thus, a recent surge of research studies has focused on understanding the mechanisms by which resident and recruited monocytes, macrophages and dendritic cells accumulate and become activated at the sites of fungal infection. Herein, we critically review how a variety of G-protein coupled chemoattractant receptors and their ligands mediate mononuclear phagocyte recruitment and effector function during infection by the most common human fungal pathogens.
Topics: Aspergillosis; CD4-Positive T-Lymphocytes; Candidiasis; Chemotactic Factors; Cryptococcosis; Dendritic Cells; Humans; Immunity, Innate; Macrophages; Monocytes; Mononuclear Phagocyte System; Mycoses; Neutrophils; Receptors, G-Protein-Coupled
PubMed: 25715741
DOI: 10.1007/s00018-015-1858-6 -
Mucosal Immunology Apr 2022In tissue, mononuclear phagocytes (MNP) are comprised of Langerhans cells, dendritic cells, macrophages and monocyte-derived cells. They are the first immune cells to... (Review)
Review
In tissue, mononuclear phagocytes (MNP) are comprised of Langerhans cells, dendritic cells, macrophages and monocyte-derived cells. They are the first immune cells to encounter HIV during transmission and transmit the virus to CD4 T cells as a consequence of their antigen presenting cell function. To understand the role these cells play in transmission, their phenotypic and functional characterisation is important. With advancements in high parameter single cell technologies, new MNPs subsets are continuously being discovered and their definition and classification is in a state of flux. This has important implications for our knowledge of HIV transmission, which requires a deeper understanding to design effective vaccines and better blocking strategies. Here we review the historical research of the role MNPs play in HIV transmission up to the present day and revaluate these studies in the context of our most recent understandings of the MNP system.
Topics: CD4-Positive T-Lymphocytes; Dendritic Cells; HIV Infections; Humans; Langerhans Cells; Macrophages; Mononuclear Phagocyte System; Phagocytes
PubMed: 35173293
DOI: 10.1038/s41385-022-00492-0 -
Mediators of Inflammation 2018Phagocytes fight fungi using canonical and noncanonical, also called LC3-associated phagocytosis (LAP), autophagy pathways. However, the outcomes of autophagy/LAP in... (Review)
Review
Phagocytes fight fungi using canonical and noncanonical, also called LC3-associated phagocytosis (LAP), autophagy pathways. However, the outcomes of autophagy/LAP in shaping host immune responses appear to greatly vary depending on fungal species and cell types. By allowing efficient pathogen clearance and/or degradation of inflammatory mediators, autophagy proteins play a broad role in cellular and immune homeostasis during fungal infections. Indeed, defects in autophagic machinery have been linked with aberrant host defense and inflammatory states. Thus, understanding the molecular mechanisms underlying the relationship between the different forms of autophagy may offer a way to identify drugable molecular signatures discriminating between selective recognition of cargo and host protection. In this regard, IFN- and anakinra are teaching examples of successful antifungal agents that target the autophagy machinery. This article provides an overview of the role of autophagy/LAP in response to fungi and in their infections, regulation, and therapeutic exploitation.
Topics: Animals; Autophagy; Humans; Interferon-gamma; Interleukin 1 Receptor Antagonist Protein; Phagocytes; Phagocytosis
PubMed: 29692681
DOI: 10.1155/2018/6195958