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Methods in Molecular Biology (Clifton,... 2019Senescent cells secrete diverse array of proteins. One group of proteins, damage-associated molecular pattern (DAMP) proteins exhibit relocalization from inside to...
Senescent cells secrete diverse array of proteins. One group of proteins, damage-associated molecular pattern (DAMP) proteins exhibit relocalization from inside to outside the cell. High Mobility Group Box 1 protein (HMGB1) is the founding DAMP member. HMGB1 relocalization from the nucleus provides a molecular signature during senescence. We provide distinct molecular techniques (immunofluorescence, immunohistochemistry, and Western blot assays) to assess HMGB1 relocalization during the initial stages of senescence.
Topics: Alarmins; Animals; Cells, Cultured; Cellular Senescence; HMGB1 Protein; Kidney; Mice; Mice, Inbred C57BL; Skin
PubMed: 30474841
DOI: 10.1007/978-1-4939-8931-7_8 -
Annual Review of Medicine Jan 2018The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor implicated in diverse chronic inflammatory states. RAGE binds and... (Review)
Review
The receptor for advanced glycation end-products (RAGE) is a multiligand pattern recognition receptor implicated in diverse chronic inflammatory states. RAGE binds and mediates the cellular response to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA. RAGE can also act as an innate immune sensor of microbial pathogen-associated molecular pattern molecules (PAMPs) including bacterial endotoxin, respiratory viruses, and microbial DNA. RAGE is expressed at low levels under normal physiology, but it is highly upregulated under chronic inflammation because of the accumulation of various RAGE ligands. Blocking RAGE signaling in cell and animal models has revealed that targeting RAGE impairs inflammation and progression of diabetic vascular complications, cardiovascular disease (CVD), and cancer progression and metastasis. The clinical relevance of RAGE in inflammatory disease is being demonstrated in emerging clinical trials of novel small-molecule RAGE inhibitors.
Topics: Alarmins; Benzamides; DNA; Glycation End Products, Advanced; HMGB1 Protein; Humans; Inflammation; Molecular Targeted Therapy; Pathogen-Associated Molecular Pattern Molecules; Receptor for Advanced Glycation End Products; S100 Proteins; Signal Transduction
PubMed: 29106804
DOI: 10.1146/annurev-med-041316-085215 -
Immunity, Inflammation and Disease Mar 2021The ubiquitously expressed nonhistone nuclear protein high-mobility group box protein 1 (HMGB1) has different functions related to posttranslational modifications and... (Review)
Review
INTRODUCTION
The ubiquitously expressed nonhistone nuclear protein high-mobility group box protein 1 (HMGB1) has different functions related to posttranslational modifications and cellular localization. In the nucleus, HMGB1 modulates gene transcription, replication and DNA repair as well as determines chromosomal architecture. When the post-transcriptional modified HMGB1 is released into the extracellular space, it triggers several physiological and pathological responses and initiates innate immunity through interacting with its reciprocal receptors (i.e., TLR4/2 and RAGE). The effect of HMGB1-mediated inflammatory activation on different systems has received increasing attention. HMGB1 is now considered to be an alarmin and participates in multiple inflammation-related diseases. In addition, HMGB1 also affects the occurrence and progression of tumors. However, most studies involving HMGB1 have been focused on adults or mature animals. Due to differences in disease characteristics between children and adults, it is necessary to clarify the role of HMGB1 in pediatric diseases.
METHODS AND RESULTS
Through systematic database retrieval, this review aimed to first elaborate the characteristics of HMGB1 under physiological and pathological conditions and then discuss the clinical significance of HMGB1 in the pediatric diseases according to different systems.
CONCLUSIONS
HMGB1 plays an important role in a variety of pediatric diseases and may be used as a diagnostic biomarker and therapeutic target for new strategies for the prevention and treatment of pediatric diseases.
Topics: Alarmins; Animals; HMGB1 Protein; Humans; Immunity, Innate; Inflammation
PubMed: 33140586
DOI: 10.1002/iid3.370 -
Cells Dec 2021Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) family that is expressed in the nuclei of endothelial and epithelial cells of barrier tissues, among... (Review)
Review
Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) family that is expressed in the nuclei of endothelial and epithelial cells of barrier tissues, among others. It functions as an alarm signal that is released upon tissue or cellular injury. IL-33 plays a central role in the initiation and amplification of type 2 innate immune responses and allergic inflammation by activating various target cells expressing its ST2 receptor, including mast cells and type 2 innate lymphoid cells. Depending on the tissue environment, IL-33 plays a wide variety of roles in parasitic and viral host defense, tissue repair and homeostasis. IL-33 has evolved a variety of sophisticated regulatory mechanisms to control its activity, including nuclear sequestration and proteolytic processing. It is involved in many diseases, including allergic, inflammatory and infectious diseases, and is a promising therapeutic target for the treatment of severe asthma. In this review, I will summarize the literature around this fascinating pleiotropic cytokine. In the first part, I will describe the basics of IL-33, from the discovery of interleukin-33 to its function, including its expression, release and signaling pathway. The second part will be devoted to the regulation of IL-33 protein leading to its activation or inactivation.
Topics: Alarmins; Animals; Humans; Inflammation; Interleukin-1; Interleukin-33; Mice, Transgenic
PubMed: 35011670
DOI: 10.3390/cells11010107 -
Immunity Mar 2023Timely labor is critical for both infant and maternal health, yet the mechanisms underlying the initiation of childbirth remain unclear. In this issue of Immunity,...
Timely labor is critical for both infant and maternal health, yet the mechanisms underlying the initiation of childbirth remain unclear. In this issue of Immunity, Siewiera et al. demonstrate a vital role for innate type 2 immune responses in controlling uterus-intrinsic onset of labor in mice..
Topics: Female; Mice; Animals; Alarmins; Interleukin-33; Uterus; Immunity, Innate
PubMed: 36921571
DOI: 10.1016/j.immuni.2023.02.007 -
Seminars in Immunology Aug 2018As main drivers of leukocyte recruitment during inflammatory reactions, chemokines act as mediatrs of alarmins in priming host defense responses after tissue exposure to... (Review)
Review
As main drivers of leukocyte recruitment during inflammatory reactions, chemokines act as mediatrs of alarmins in priming host defense responses after tissue exposure to toxic or infectious agents, immunomediated damage, and in inflammation-driven tumors. Chemokines can therefore be considered alarm signals generated by tissues in a broad number of conditions, and mechanisms controlling chemokines biological activities are therefore key to regulate tissue reactions induced by alarmins. By transporting, presenting or scavenging different sets of chemokines, atypical chemokine receptors represent an emerign subfamily of chemokine receptors which operates in tissues as chemokine gatekeepers in order to establish and shape their gradients and coordinate leukocyte recruitment.
Topics: Alarmins; Animals; Chemokines; Humans; Inflammation; Leukocytes; Models, Immunological; Neoplasms; Receptors, Chemokine; Signal Transduction
PubMed: 30337241
DOI: 10.1016/j.smim.2018.10.005 -
Frontiers in Immunology 2020The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and... (Review)
Review
The NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome is an oligomeric complex comprised of the NOD-like receptor NLRP3, the adaptor ASC, and caspase-1. This complex is crucial to the host's defense against microbes as it promotes IL-1β and IL-18 secretion and induces pyroptosis. NLRP3 recognizes variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) generated during viral replication that triggers the NLRP3 inflammasome-dependent antiviral immune responses and facilitates viral eradication. Meanwhile, several viruses have evolved elaborate strategies to evade the immune system by targeting the NLRP3 inflammasome. In this review, we will focus on the crosstalk between the NLRP3 inflammasome and viruses, provide an overview of viral infection-induced NLRP3 inflammasome activation, and the immune escape strategies of viruses through their modulation of the NLRP3 inflammasome activity.
Topics: Alarmins; Animals; Humans; Immune Evasion; Inflammasomes; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pathogen-Associated Molecular Pattern Molecules; Signal Transduction; Virus Diseases; Viruses
PubMed: 32133002
DOI: 10.3389/fimmu.2020.00211 -
Theranostics 2023Resistance to 5-fluorouracil (5-FU) chemotherapy remains the main barrier to effective clinical outcomes for patients with colorectal cancer (CRC). A better...
Resistance to 5-fluorouracil (5-FU) chemotherapy remains the main barrier to effective clinical outcomes for patients with colorectal cancer (CRC). A better understanding of the detailed mechanisms underlying 5-FU resistance is needed to increase survival. Interleukin (IL)-33 is a newly discovered alarmin-like molecule that exerts pro- and anti-tumorigenic effects in various cancers. However, the precise role of IL-33 in CRC progression, as well as in the development of 5-FU resistance, remains unclear. High-quality RNA-sequencing analyses were performed on matched samples from patients with 5-FU-sensitive and 5-FU-resistant CRC. The clinical and biological significance of IL-33, including its effects on both T cells and tumor cells, as well as its relationship with 5-FU chemotherapeutic activity were examined in , and models of CRC. The molecular mechanisms underlying these processes were explored. IL-33 expressed by tumor cells was a dominant mediator of antitumoral immunity in 5-FU-sensitive patients with CRC. By binding to its ST2 receptor, IL-33 triggered CD4+ (Th1 and Th2) and CD8+ T cell responses by activating annexin A1 downstream signaling cascades. Mechanistically, IL-33 enhanced the sensitivity of CRC cells to 5-FU only in the presence of T cells, which led to the activation of both tumor cell-intrinsic apoptotic and immune killing-related signals, thereby synergizing with 5-FU to induce apoptosis of CRC cells. Moreover, injured CRC cells released more IL-33 and the T cell chemokines CXCL10 and CXCL13, forming a positive feedback loop to further augment T cell responses. Our results identified a previously unrecognized connection between IL-33 and enhanced sensitivity to 5-FU. IL-33 created an immune-active tumor microenvironment by orchestrating antitumoral T cell responses. Thus, IL-33 is a potential predictive biomarker for 5-FU chemosensitivity and favorable prognosis and has potential as a promising adjuvant immunotherapy to improve the clinical benefits of 5-FU-based therapies in the treatment of CRC.
Topics: Humans; Fluorouracil; Alarmins; Colorectal Neoplasms; Interleukin-33; Cell Line, Tumor; Drug Resistance, Neoplasm; Tumor Microenvironment
PubMed: 37056569
DOI: 10.7150/thno.80483 -
Journal of Cellular Physiology May 2021High-mobility group box 1 (HMGB1) was initially recognized as a ubiquitous nuclear protein involved in maintaining the nucleosome integrity and facilitating gene... (Review)
Review
High-mobility group box 1 (HMGB1) was initially recognized as a ubiquitous nuclear protein involved in maintaining the nucleosome integrity and facilitating gene transcription. HMGB1 has since been reevaluated to be a prototypical damage-associated molecular pattern (DAMP) protein, and together with its exogenous counterpart, pathogen-associated molecular pattern (PAMP), completes the body's alarmin system against disturbances in homeostasis. HMGB1 can be released into the extracellular matrix (ECM) by either granulocytes or necrotic cells to serve as a chemotaxis/cytokine during infection, endotoxemia, hypoxia, ischemia-reperfusion events, and cancer. Different isoforms of HMGB1 present with distinctive physiological functions in ECM-fully-reduced HMGB1 (all thiol) acts as the initial damage signal to recruit circulating myeloid cells, disulfide HMGB1 behaves as a cytokine to activate macrophages and neutrophils, and both signals are turned off when HMGB1 is terminally oxidized into the final sulfonate form. Targeting HMGB1 constitutes a favorable therapeutic strategy for inflammation and inflammatory diseases. Antagonists such as ethyl pyruvate inhibit HMGB1 by interfering with its cytoplasmic exportation, while others such as glycyrrhizin directly bind to HMGB1 and render it unavailable for its receptors. The fact that a mixture of different HMGB1 isoforms is present in the ECM poses a challenge in pinpointing the exact role of an individual antagonist. A more discriminative probe for HMGB1 may be necessary to advance our knowledge of HMGB1, HMGB1 antagonists, and inflammatory-related diseases.
Topics: Alarmins; Animals; Cytokines; Endotoxemia; HMGB1 Protein; Humans; Inflammation; Macrophages
PubMed: 33107103
DOI: 10.1002/jcp.30125 -
Current Opinion in Immunology Feb 2016Alarmins are a heterogeneous group of endogenous molecules that signal cellular damage when sensed extracellularly. Heme is an endogenous molecule that acts as a... (Review)
Review
Alarmins are a heterogeneous group of endogenous molecules that signal cellular damage when sensed extracellularly. Heme is an endogenous molecule that acts as a prosthetic group of hemoproteins, such as hemoglobin and myoglobin. When released from damaged red blood cells or muscle cells, oxidized hemoglobin and myoglobin release their prosthetic heme groups, respectively. This generates labile heme, which is sensed by pattern recognition receptors (PRR) expressed by innate immune cells and possibly regulatory T cells (TREG). The ensuing adaptive response, which alerts for the occurrence of red blood cell or muscle cell damage, regulates the pathologic outcome of hemolysis or rhabdomyolysis, respectively. In conclusion, we propose that labile heme is an alarmin.
Topics: Adaptive Immunity; Alarmins; Animals; Endothelial Cells; Erythrocytes; Gene Expression Regulation; Heme; Humans; Immunity, Innate; Macrophages; Muscle Cells; Neutrophils; Reactive Oxygen Species; Receptors, Pattern Recognition; Signal Transduction
PubMed: 26741528
DOI: 10.1016/j.coi.2015.11.006