Alarmins

During sepsis, the alarmin HMGB1 is released from tissues and promotes systemic inflammation that results in multi-organ damage, with the kidney particularly susceptible to injury. The severity of inflammation and pro-damage signaling mediated by HMGB1 appears to be dependent on the alarmin's redox state. Therefore, we examined HMGB1 redox in kidney cells during sepsis. Using intravital microscopy, CellROX labeling of kidneys in live mice indicated increased ROS generation in the kidney perivascular endothelium and tubules during lipopolysaccharide (LPS)-induced sepsis...

The macrophage-inducible C-type lectin (Mincle) is an innate immune receptor on myeloid cells sensing diverse entities including pathogens and damaged cells. Mincle was first described as a receptor for the mycobacterial cell wall glycolipid, trehalose-6,6'-dimycolate, or cord factor, and the mammalian necrotic cell-derived alarmin histone deacetylase complex unit Sin3-associated protein 130. Upon engagement by its ligands, Mincle induces secretion of innate cytokines and other immune mediators modulating inflammation and immunity...

BACKGROUND: Alarmins, endogenous molecules released on tissue damage have been shown to play an important role in inflammatory musculoskeletal conditions including fracture repair andrheumatoid arthritis. However, the contribution of alarmins to the pathogenesis of tendon disease is not fully understood. METHODS: We investigated expression of alarmin proteins (S100A9, high-mobility group box 1 (HMGB1) and interleukin-33 (IL-33) and hypoxia-inducible factor 1α (HIF-1α), a subunit of an oxygen sensitive transcription factor, in three cohorts of human supraspinatus tissues: healthy (n=6), painful diseased (n=13) and post-treatment pain-free tendon samples (n=5)...

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The deleterious impact of concomitant muscle injury on fracture healing and limb function is commonly considered part of the natural sequela of orthopedic trauma. Recent reports suggest that heightened inflammation in the surrounding traumatized musculature is a primary determinant of fracture healing. Relatedly, there are emerging potential therapeutic approaches for severe muscle trauma (e.g., volumetric muscle loss [VML] injury), such as autologous minced muscle grafts (1 mm(3) pieces of muscle; GRAFT), that can partially prevent chronic functional deficits and appear to have an immunomodulatory effect within VML injured muscle...

Atherosclerosis is a chronic inflammatory disease resulting in the formation of the atherosclerotic plaque. Plaque formation starts with the inflammation in fatty streak and progress through atheroma, atheromatous plaque, and fibroatheroma leading to development of stable plaque. Hypercholesterolemia, dyslipidemia, hyperglycemia are the risk factors for atherosclerosis. Inflammation, infection with viruses and bacteria, and dysregulation in the endothelial and vascular smooth muscle cells leads to advanced plaque formation...

BACKGROUND: The immunosuppression and immune dysregulation that follows severe injury includes type 2 immune responses manifested by elevations in interleukin (IL) 4, IL5, and IL13 early after injury. We hypothesized that IL33, an alarmin released early after tissue injury and a known regulator of type 2 immunity, contributes to the early type 2 immune responses after systemic injury. METHODS AND FINDINGS: Blunt trauma patients admitted to the trauma intensive care unit of a level I trauma center were enrolled in an observational study that included frequent blood sampling...

PURPOSE: Dying cells release endogenous molecules known as alarmins that signal danger to surrounding tissue. We investigated the effects of necrotic cell-derived alarmins on cytokine expression and barrier function in human corneal epithelial cells. METHODS: The release of interleukin (IL)-6 and IL-8 from immortalized human corneal epithelial (HCE) cells in culture was measured with enzyme-linked immunosorbent assays. The abundance of IL-6 and 8 mRNAs was quantitated by reverse transcription and real-time polymerase chain reaction analysis...

The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter...

The alarmin IL-33 is an IL-1 family member that stimulates pleiotropic immune reactions depending on the target tissue and microenvironmental factors. In this study, we have investigated the role of IL-33/ST2 axis in antitumor response to melanoma. Injection of IL-33 in mice-bearing subcutaneous B16.F10 melanoma resulted in significant tumor growth delay. This effect was associated with intratumoral accumulation of CD8(+) T cells and eosinophils, decrease of immunosuppressive myeloid cells, and a mixed Th1/Th2 cytokine expression pattern with local and systemic activation of CD8(+) T and NK cells...

Biceps tendinopathy is a relatively common ailment that typically presents as pain, tenderness, and weakness in the tendon of the long head of the biceps brachii. Though it is often associated with degenerative processes of the rotator cuff and the joint, this is not always the case, thus, the etiology remains considerably unknown. There has been recent interest in elucidating the pathogenesis of tendinopathy, since it can be an agent of chronic pain, and is difficult to manage. The purpose of this article is to critically evaluate relevant published research that reflects the current understanding of pain and how it relates to biceps tendinopathy...

Although interleukin (IL)-33, a member of the IL-1 cytokine family, plays pro-inflammatory roles in immune cells as an "alarmin", little is known regarding the biological actions of IL-33 on vascular endothelial cells. To investigate the effects of IL-33 on vascular endothelial cells, we first screened the IL-33-regulated proteins in human umbilical vein endothelial cells (HUVECs) using a dot blot array, and observed that IL-33 markedly increased growth-regulated oncogene (GRO)-α, a chemokine that is also known as CXCL1...

BACKGROUND: Recently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders. Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated to airway hyper-responsiveness and airway inflammation. OBJECTIVE: This literature review aims to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma...

Obesity has emerged as an imminent global public health concern over the past several decades. It has now become evident that obesity is characterized by the persistent and low-grade inflammation in the adipose tissue, and serves as an independent risk factor for many metabolic disorders such as diabetes and cardiovascular disease. Particularly, adipocytes originated from obese mice and humans likely predominate necrosis upon stressful insults, leading to passive release of cellular contents including the high mobility group box 1 (HMGB1) into the extracellular milieu...

Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. Although type 2 responses are implicated in AD, emerging evidence indicates a potential role for the IL-17A signaling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency (Il17ra(-/-) ) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra(-/-) mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, as well as increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin...

Sepsis is a life-threatening condition that requires urgent care. Thus, the identification of specific and sensitive biomarkers for its early diagnosis and management are of clinical importance. The alarmin prothymosin alpha (proTα) and its decapeptide proTα(100-109) are immunostimulatory peptides related to cell death. In this study, we generated bacterial models of sepsis in mice using two Klebsiella pneumoniae strains (L-78 and ATCC 43816) and monitored sepsis progression using proTα(100-109) as a biomarker...

The alarmin IL-33 has been described to be upregulated in human and murine viral hepatitis. However, the role of endogenous IL-33 in viral hepatitis remains obscure. We aimed to decipher its function by infecting IL-33-deficient mice (IL-33 KO) and their wild-type (WT) littermates with pathogenic mouse hepatitis virus (L2-MHV3). The IL-33 KO mice were more sensitive to L2-MHV3 infection exhibiting higher levels of AST/ALT, higher tissue damage, significant weight loss, and earlier death. An increased depletion of B and T lymphocytes, NKT cells, dendritic cells, and macrophages was observed 48 h postinfection (PI) in IL-33 KO mice than that in WT mice...

Severe inflammatory complications are a potential consequence in patients with predetermined conditions of infections, pulmonary diseases, or cardiovascular disorders. Notably, the amplitude of the inflammatory response towards these complications can dictate the disease progression and outcome. During the recent years, evidence from basic research as well as from clinical studies has identified self-extracellular nucleic acids as important players in the crosstalk between immunity and cardiovascular diseases...

Osteoarthritis (OA) is a degenerative disease characterized by the destruction of cartilage. The greatest risk factors for the development of OA include age and obesity. Recent studies suggest the role of inflammation in the pathogenesis of OA. The two most common locations for OA to occur are in the knee and hip joints. The knee joint experiences more mechanical stress, cartilage degeneration, and inflammation than the hip joint. This could contribute to the increased incidence of OA in the knee joint. Damage-associated molecular patterns (DAMPs), including high-mobility group box-1, receptor for advanced glycation end products, and alarmins (S100A8 and S100A9), are released in the joint in response to stress-mediated chondrocyte and cartilage damage...

INTRODUCTION: Interleukin-33 (IL-33) is a cell damage-induced alarmin. The plasma concentration of suppression of tumorogenicity (sST2), a surrogate marker of IL-33 production, is a prognostic marker of cardiovascular disease. OBSERVATION: Recently, we reported that sST2 plasma levels were elevated in early HIV-1 infection and linked to markers of microbial translocation and of T cell activation. RESULTS: Here we show that it is not the case in patients with suppressed viremia...