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American Journal of Respiratory and... Feb 2022
Topics: Alarmins; Asthma; Cytokines; Humans
PubMed: 34936856
DOI: 10.1164/rccm.202111-2571ED -
Nature Communications Nov 2023As the primary site of T-cell development, the thymus dictates immune competency of the host. The rates of thymus function are not constant, and thymus regeneration is...
As the primary site of T-cell development, the thymus dictates immune competency of the host. The rates of thymus function are not constant, and thymus regeneration is essential to restore new T-cell production following tissue damage from environmental factors and therapeutic interventions. Here, we show the alarmin interleukin (IL) 33 is a product of Sca1 thymic mesenchyme both necessary and sufficient for thymus regeneration via a type 2 innate immune network. IL33 stimulates expansion of IL5-producing type 2 innate lymphoid cells (ILC2), which triggers a cellular switch in the intrathymic availability of IL4. This enables eosinophil production of IL4 to re-establish thymic mesenchyme prior to recovery of thymopoiesis-inducing epithelial compartments. Collectively, we identify a positive feedback mechanism of type 2 innate immunity that regulates the recovery of thymus function following tissue injury.
Topics: Interleukin-33; Alarmins; Immunity, Innate; Interleukin-4; Lymphocytes
PubMed: 37938566
DOI: 10.1038/s41467-023-43072-x -
Immunotherapy 2015
Review
Topics: Alarmins; Animals; Antineoplastic Combined Chemotherapy Protocols; Dendritic Cells; Gene Expression Regulation, Neoplastic; HMGN1 Protein; Humans; Immunomodulation; Lymphocyte Activation; Neoplasms; Th1 Cells; Tumor Microenvironment
PubMed: 26567750
DOI: 10.2217/imt.15.76 -
Translational Research : the Journal of... Dec 2018Mitochondria are functionally versatile organelles. In addition to their conventional role of meeting the cell's energy requirements, mitochondria also actively regulate... (Review)
Review
Mitochondria are functionally versatile organelles. In addition to their conventional role of meeting the cell's energy requirements, mitochondria also actively regulate innate immune responses against infectious and sterile insults. Components of mitochondria, when released or exposed in response to dysfunction or damage, can be directly recognized by receptors of the innate immune system and trigger an immune response. In addition, despite initiation that may be independent from mitochondria, numerous innate immune responses are still subject to mitochondrial regulation as discrete steps of their signaling cascades occur on mitochondria or require mitochondrial components. Finally, mitochondrial metabolites and the metabolic state of the mitochondria within an innate immune cell modulate the precise immune response and shape the direction and character of that cell's response to stimuli. Together, these pathways result in a nuanced and very specific regulation of innate immune responses by mitochondria.
Topics: Alarmins; Animals; DNA, Mitochondrial; Humans; Immunity, Innate; Mitochondria; Models, Biological; Signal Transduction
PubMed: 30165038
DOI: 10.1016/j.trsl.2018.07.014 -
Current Medicinal Chemistry 2017Prothymosin alpha (proTα) is a ubiquitous polypeptide first isolated by Haritos in 1984, whose role still remains partly elusive. We know that proTα acts both,... (Review)
Review
BACKGROUND/OBJECTIVE
Prothymosin alpha (proTα) is a ubiquitous polypeptide first isolated by Haritos in 1984, whose role still remains partly elusive. We know that proTα acts both, intracellularly, as an anti-apoptotic and proliferation mediator, and extracellularly, as a biologic response modifier mediating immune responses similarly to molecules termed as "alarmins". Our research team pioneered the elucidation of the mechanisms underlying the observed activities of proTα.
RESULTS
We were the first to demonstrate that proTα levels increase during normal and abnormal cell proliferation. We showed that proTα acts pleiotropically, inducing immunomodulatory effects on immune cell populations. We revealed that the immunoreactive region of proTα is the carboxyterminal decapeptide proTα(100-109) and both molecules stimulate innate immune responses, signaling through Toll-like receptors (TLRs), specifically TLR-4. We reported that proTα and proTα(100-109) bind on the surface of human neutrophils on sites involving TLR-4, and cell activation is complemented by cytoplasmic calcium ion influx. Further, we showed that proTα and proTα(100-109) act as adjuvants upstream of lymphocyte stimulation and, in the presence of antigen, promote the expansion of antigen-reactive effectors. Most recently, we reported that proTα(100-109) may accumulate in experimentally inflamed sites and can serve as a surrogate biomarker in severe bacterial infections, proposing that extracellular release of proTα or proTα(100- 109) alerts the immune system during conditions of danger.
CONCLUSION
We, therefore, suggest that proTα, and likely proTα(100-109), act as alarmins, being important immune mediators as well as biomarkers, and could eventually become targets for new therapeutic/diagnostic approaches in immune-related diseases like cancer, inflammation, and sepsis.
Topics: Alarmins; Autoimmune Diseases; Humans; Immunity, Innate; Killer Cells, Natural; Neoplasms; Protein Precursors; Sepsis; T-Lymphocytes; Thymosin; Toll-Like Receptors
PubMed: 28521686
DOI: 10.2174/0929867324666170518110033 -
Annual Review of Pathology Jan 2020Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific... (Review)
Review
Recognizing the importance of leukocyte trafficking in inflammation led to some therapeutic breakthroughs. However, many inflammatory pathologies remain without specific therapy. This review discusses leukocytes in the context of sterile inflammation, a process caused by sterile (non-microbial) molecules, comprising damage-associated molecular patterns (DAMPs). DAMPs bind specific receptors to activate inflammation and start a highly optimized sequence of immune cell recruitment of neutrophils and monocytes to initiate effective tissue repair. When DAMPs are cleared, the recruited leukocytes change from a proinflammatory to a reparative program, a switch that is locally supervised by invariant natural killer T cells. In addition, neutrophils exit the inflammatory site and reverse transmigrate back to the bloodstream. Inflammation persists when the program switch or reverse transmigration fails, or when the coordinated leukocyte effort cannot clear the immunostimulatory molecules. The latter causes inappropriate leukocyte activation, a driver of many pathologies associated with poor lifestyle choices. We discuss lifestyle-associated inflammatory diseases and their corresponding immunostimulatory lifestyle-associated molecular patterns (LAMPs) and distinguish them from DAMPs.
Topics: Alarmins; Animals; Biological Factors; Environmental Biomarkers; Humans; Immunity; Immunity, Innate; Inflammation; Life Style; Neutrophils; Pathogen-Associated Molecular Pattern Molecules
PubMed: 31675482
DOI: 10.1146/annurev-pathmechdis-012419-032847 -
Current Opinion in Microbiology Aug 2016Fungi encounter numerous stresses in a mammalian host, including the immune system, which they must adapt to in order to grow and cause disease. The host immune system... (Review)
Review
Fungi encounter numerous stresses in a mammalian host, including the immune system, which they must adapt to in order to grow and cause disease. The host immune system tunes its response to the threat level posed by the invading pathogen. We discuss recent findings on how interleukin (IL)-1 signaling is central to tuning the immune response to the virulence potential of invasive fungi, as well as other pathogens. Moreover, we discuss fungal factors that may drive tissue invasion and destruction that regulate IL-1 cytokine release. Moving forward understanding the mechanisms of fungal adaption to the host, together with understanding how the host innate immune system recognizes invading fungal pathogens will increase our therapeutic options for treatment of invasive fungal infections.
Topics: Alarmins; Animals; Aspergillosis; Aspergillus; Candida; Candidiasis; Host-Pathogen Interactions; Immunity, Innate; Interleukin-1; Invasive Fungal Infections; Signal Transduction
PubMed: 27351354
DOI: 10.1016/j.mib.2016.06.002 -
Seminars in Immunology Aug 2018
Review
Topics: Alarmins; Animals; Antibodies, Neutralizing; Humans; Interleukin-1alpha; Intracellular Space; Neoplasms; Treatment Outcome; Tumor Microenvironment
PubMed: 30554608
DOI: 10.1016/j.smim.2018.10.006 -
Frontiers in Immunology 2020High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and... (Review)
Review
High mobility group box 1 (HMGB1) is a highly conserved, nuclear protein present in all cell types. It is a multi-facet protein exerting functions both inside and outside of cells. Extracellular HMGB1 has been extensively studied for its prototypical alarmin functions activating innate immunity, after being actively released from cells or passively released upon cell death. TLR4 and RAGE operate as the main HMGB1 receptors. Disulfide HMGB1 activates the TLR4 complex by binding to MD-2. The binding site is separate from that of LPS and it is now feasible to specifically interrupt HMGB1/TLR4 activation without compromising protective LPS/TLR4-dependent functions. Another important therapeutic strategy is established on the administration of HMGB1 antagonists precluding RAGE-mediated endocytosis of HMGB1 and HMGB1-bound molecules capable of activating intracellular cognate receptors. Here we summarize the role of HMGB1 in inflammation, with a focus on recent findings on its mission as a damage-associated molecular pattern molecule and as a therapeutic target in inflammatory diseases. Recently generated HMGB1-specific inhibitors for treatment of inflammatory conditions are discussed.
Topics: Alarmins; Animals; Antigens, Neoplasm; HMGB1 Protein; Humans; Immunity, Innate; Inflammation; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Signal Transduction; Toll-Like Receptor 4
PubMed: 32265930
DOI: 10.3389/fimmu.2020.00484 -
Frontiers in Immunology 2019Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the... (Review)
Review
Sepsis is a deadly inflammatory syndrome caused by an exaggerated immune response to infection. Much has been focused on host response to pathogens mediated through the interaction of pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs). PRRs are also activated by host nuclear, mitochondrial, and cytosolic proteins, known as damage-associated molecular patterns (DAMPs) that are released from cells during sepsis. Some well described members of the DAMP family are extracellular cold-inducible RNA-binding protein (eCIRP), high mobility group box 1 (HMGB1), histones, and adenosine triphosphate (ATP). DAMPs are released from the cell through inflammasome activation or passively following cell death. Similarly, neutrophil extracellular traps (NETs) are released from neutrophils during inflammation. NETs are webs of extracellular DNA decorated with histones, myeloperoxidase, and elastase. Although NETs contribute to pathogen clearance, excessive NET formation promotes inflammation and tissue damage in sepsis. Here, we review DAMPs and NETs and their crosstalk in sepsis with respect to their sources, activation, release, and function. A clear grasp of DAMPs, NETs and their interaction is crucial for the understanding of the pathophysiology of sepsis and for the development of novel sepsis therapeutics.
Topics: Adenosine Triphosphate; Alarmins; Animals; Disease Susceptibility; Extracellular Traps; HMGB1 Protein; Histones; Humans; Neutrophils; Protein Binding; Sepsis; Signal Transduction
PubMed: 31736963
DOI: 10.3389/fimmu.2019.02536