Damage-Associated Molecular Patterns in Human Diseases

This paper presents a study of the flow of ice in wedge-shaped converging channels. Such flows are encountered in the relatively constricted waters of the Canadian Arctic Archipelago. Ridging, lead opening patterns, development of a highpressure area, and arch formation are some of the processes which take place during ice flow through converging channels. An idealized geometry and steady wind forcing were used in the testing. The results give ice cover velocity, distribution of stresses, ice thickness, area coverage and ridging. Some of the conditions leading to arch formation at the constricted exit of the channel are explored.

From the Editor’s desk....: September 2018

The conventional role of the immune system has been viewed as the first line of defence discriminating self from nonself. However, in the past decade, the innate immune response has proven to be more advanced sensing signals of danger, such as pathogen‐specific molecules ( PAMPs , pathogen‐associated molecular patterns) or endogenous host‐derived signals released during cellular damage, while remaining unresponsive to normal host molecules, dietary antigens or commensal bacteria. The host response to invading microbial pathogens relies on both the innate and adaptive immune response. The danger theory of Matzinger (1994) proposed a similar model for the adaptive immune response in discriminating self from nonself. This theory proposed that the immune system does not react to foreign substances but instead responds to situations that are potentially harmful. These danger signals, or damage‐associated molecular patterns ( DAMPs ), released by damaged cells, can provide for a second signal which is necessary to activate the immune response while avoiding collateral damage in situations in which harmless nonself is present. Key Concepts According to the danger theory of Matzinger, the immune system does not merely distinguish whether an entity is foreign or not, it mainly determines whether it will cause damage to the body. Damage‐associated molecular patterns (DAMP) are danger signals released during inflammatory stress such as burns, trauma and infection. Each pathogen is recognised by its specific molecular signature or pathogen‐associated molecular pattern (PAMP). Activation of the innate immune system relies on both pathogen‐specific molecules and endogenous danger signals. DAMPs can be recognised by pattern‐recognition receptors on antigen‐presenting cells or by distinct receptors such as the receptor for advanced glycation end products (RAGE). Key DAMPs that are recognised by Toll‐like receptors (TLRs) include heat shock proteins (HSPs), high‐mobility group box 1 (HMGB)‐1 and the S100 proteins.

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

Mitochondria, vital cellular power plants to generate energy, are involved in immune responses. Mitochondrial damage-associated molecular patterns (DAMPs) are molecules that are released from mitochondria to extracellular space during cell death and include not only proteins but also DNA or lipids. Mitochondrial DAMPs induce inflammatory responses and are critically involved in the pathogenesis of various diseases. Recent studies elucidate the molecular mechanisms by which mitochondrial DAMPs are released and initiate immune responses by use of genetically modulated cells or animals. Importantly, the levels of mitochondrial DAMPs in patients are often associated with severity and prognosis of human diseases, such as infection, asthma, ischemic heart disease, and cancer. Although mitochondrial DAMPs can represent proinflammatory molecules in various experimental models, their roles in human diseases may be multifunctional and complex. It remains unclear where and how mitochondrial DAMPs are liberated into extracellular spaces and exert their biological functions particularly in vivo. In addition, while mitochondria can secrete several types of DAMPs during cell death, the interaction of each mitochondrial DAMP (e.g., synergistic effects) remains unclear. Regulation of mitochondrial DAMP-mediated immune responses may be important to alter the progression of human diseases. In addition, measuring mitochondrial DAMPs in patients may be clinically useful as biomarkers to predict prognosis or response to therapies. Further studies of the mechanisms by which mitochondrial DAMPs impact the initiation and progression of diseases may lead to the development of therapeutics specifically targeting this pathway. Antioxid.

1. Arthritis can be induced in rodents by priming T-cells to respond to a foreign antigen and then challenging with antigen intra-articularly. This may be a model of the situation in human reactive arthritis in which T-cell responses are induced by antigens from organisms which trigger reactive arthritis (e.g. Chlamydia trachomatis) and antigen finds its way to the joint, most probably within macrophages. Priming by previous exposure to antigens similar to those of the triggering organism could also play a part in pathogenesis. Genetic factors determining the nature and control of the immune response affect the severity and duration of the arthritis. 2. T-cell-dependent arthritis can be induced in rodents by immunization with an antigen known to be expressed in the joint (e.g. Type II collagen). Whether this is an important mechanism in human arthritis is still unclear, even though diseases such as rheumatoid arthritis are conventionally thought of as 'autoimmune'. No convincing candidate autoantigen has yet been identified in rheumatoid arthritis, and recent experiments in transgenic mice indicate that arthritis can be induced by an autoimmune T-cell response which does not target an antigen confined to the joint. 3. Adjuvant arthritis is a classical T-cell-dependent animal model of human arthritis; recently arthritis has been described as a rare complication in patients receiving adjuvant (intra-vesical live BCG organisms) for bladder cancer. Increasing attention is being paid to the role of adjuvants as 'danger signals', which allow the immune system to determine whether an antigenic challenge poses a threat. Inappropriate attachment of danger signals to self antigens may result in T-cell-mediated immune responses, which could play a part in the pathogenesis of arthritis. 4. Animal studies indicate that autoimmune/inflammatory diseases can be produced by imbalances within T-cell populations, and that certain T-cells also have the capacity to regulate inflammatory responses. Among the latter are T-cells specific for conserved epitopes within heat shock protein 60. The extent to which T-cells of this kind operate in human disease has yet to be determined.

Damage-associated molecular patterns (DAMPs) are typically derived from the endogenous elements of necrosis cells and can trigger inflammatory responses by activating DAMPs-sensing receptors on immune cells. Failure to clear DAMPs may lead to persistent inflammation, thereby contributing to the pathogenesis of immunological diseases. This review focuses on a newly recognized class of DAMPs derived from lipid, glucose, nucleotide, and amino acid metabolic pathways, which are then termed as metabolite-derived DAMPs. This review summarizes the reported molecular mechanisms of these metabolite-derived DAMPs in exacerbating inflammation responses, which may attribute to the pathology of certain types of immunological diseases. Additionally, this review also highlights both direct and indirect clinical interventions that have been explored to mitigate the pathological effects of these DAMPs. By summarizing our current understanding of metabolite-derived DAMPs, this review aims to inspire future thoughts and endeavors on targeted medicinal interventions and the development of therapies for immunological diseases.

Strategies to Modulate Immune Responses: A New Frontier for Gene Therapy

Danger Theory is presented with particular predominance on analogies in the Artificial Immune Systems world. Artificial Immune System (AIS) is relatively naive paradigm for intelligent computations. The inspiration for AIS is derived from natural Immune System (IS). The idea is that the artificial cells release signals describing their status, e.g., safe signals and danger signals. The various artificial cells use the signals in order to adapt their behavior. This new theory suggests that the immune system reacts to threats based on the correlation of various (danger) signals and it provides a method of ‘grounding’ the immune response, i.e., linking it directly to the attacker. In this paper, we look at Danger Theory from the perspective of AIS practitioners and an overview of the Danger Theory is presented with particular emphasis on analogies in the Artificial Immune Systems world.

Significance: We proposed lysophospholipids (LPLs) and LPL-G-protein-coupled receptors (GPCRs) as conditional danger-associated molecular patterns (DAMPs) and conditional DAMP receptors as a paradigm shift to the widely accepted classical DAMP and DAMP receptor model. Recent Advances: The aberrant levels of LPLs and GPCRs activate pro-inflammatory signal transduction pathways, trigger innate immune response, and lead to tissue oxidative and inflammatory injury. Critical Issues: Classical DAMP model specifies only the endogenous metabolites that are released from damaged/dying cells as DAMPs, but fails to identify elevated endogenous metabolites secreted from viable/live cells during pathologies as DAMPs. The current classification of DAMPs also fails to clarify the following concerns: (i) Are molecules, which bind to pattern recognition receptors (PRRs), the only DAMPs contributing to inflammation and tissue injury? (ii) Are all DAMPs acting only via classical PRRs during cellular stress? To answer these questions, we reviewed the molecular characteristics and signaling mechanisms of LPLs, a group of endogenous metabolites and their specific receptors and analyzed the significant progress achieved in characterizing oxidative stress mechanisms of LPL mediated tissue injury. Future Directions: Further LPLs and LPL-GPCRs may serve as potential therapeutic targets for the treatment of pathologies induced by sterile inflammation. Antioxid. Redox Signal. 28, 973-986.

Since the discovery of viroids as smallest RNA pathogens causing plant infection, researchers have been fascinated by how these tiny RNAs invade plants and cause disease. Initially, it was thought that viroids caused disease through their interactions with the host's proteins. However, later studies suggested that RNA interference (RNAi) might play a role in viroid pathogenesis. There's still uncertainty about whether viroids can be detected at the cell membrane by specific receptors, similar to how bacterial and fungal pathogens are recognized. Hence, a key question has been whether viroid can act as Damage-associated molecular patterns (DAMPs) or Pathogen-associated molecular patterns (PAMPs), which could trigger the plant's immune responses, remained a debated topic. Recent findings, including advancements in transcriptomics, show that the plant's innate immune responses can be activated during viroid infection. The discovery of virus-derived double-stranded RNA (dsRNA) acting as DAMPs, which triggers immune responses through somatic embryogenesis receptor-like kinase 1 (SERK1)-mediated plasmodesmal immunity, suggests that viroids might indeed be recognized at the plant cell membrane. This review aims to clarify how viroids are detected by the plant immune system, the immune responses triggered by their entry, and the effects of viroid infection on plant cellular and molecular processes. Understanding RNA-triggered immunity related to viroids can help in developing plants that are resistant or tolerant to these pathogens.

Severe or major burns induce a pathophysiological, immune, and inflammatory response that can persist for a long time and affect morbidity and mortality. Severe burns are followed by a “hypermetabolic response”, an inflammatory process that can be extensive and become uncontrolled, leading to a generalized catabolic state and delayed healing. Catabolism causes the upregulation of inflammatory cells and innate immune markers in various organs, which may lead to multiorgan failure and death. Burns activate immune cells and cytokine production regulated by damage-associated molecular patterns (DAMPs). Trauma has similar injury-related immune responses, whereby DAMPs are massively released in musculoskeletal injuries and elicit widespread systemic inflammation. Hemorrhagic shock is the main cause of death in trauma. It is hypovolemic, and the consequence of volume loss and the speed of blood loss manifest immediately after injury. In burns, the shock becomes evident within the first 24 h and is hypovolemic-distributive due to the severely compromised regulation of tissue perfusion and oxygen delivery caused by capillary leakage, whereby fluids shift from the intravascular to the interstitial space. In this review, we compare the pathophysiological responses to burns and trauma including their associated clinical patterns.

Cellular damage inflicted by wounding, pathogen infection, and herbivory releases a variety of host-derived metabolites, degraded structural components, and peptides into the extracellular space that act as alarm signals when perceived by adjacent cells. These so-called damage-associated molecular patterns (DAMPs) function through plasma membrane localized pattern recognition receptors to regulate wound and immune responses. In plants, DAMPs act as elicitors themselves, often inducing immune outputs such as calcium influx, reactive oxygen species generation, defense gene expression, and phytohormone signaling. Consequently, DAMP perception results in a priming effect that enhances resistance against subsequent pathogen infections. Alongside their established function in local tissues, recent evidence supports a critical role of DAMP signaling in generation and/or amplification of mobile signals that induce systemic immune priming. Here, we summarize the identity, signaling, and synergy of proposed and established plant DAMPs, with a focus on those with published roles in systemic signaling.

Autoimmunity--promoting and stabilizing innate immunity 'UNWUCHT'.

Recognition of nucleic acids as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) promotes an inflammatory response. On the other hand, LL-37, an antimicrobial peptide, is a multifunctional modulator of immune response, though whether it modulates inflammatory responses induced by nucleic acids in oral keratinocytes is unknown. In this study, we firstly investigated the effect of LL-37 on CXCL10 induced by DAMPs and PAMPs in immortalized oral keratinocytes, RT7. Furthermore, the effects of LL-37 on translocation of exogenous nucleic acids into cytoplasm as well as cytosolic receptor, RIG-I on immune responses mediated by LL-37-nucleic acid complexes were examined. From these results, LL-37 enhanced necrotic cell supernatant (NCS)-induced CXCL10 expression in RT7, while the response was decreased by RNase. Complexes of LL-37 and double-stranded (ds) RNA, Poly(I:C) enhanced CXCL10 expression in comparison with each alone, which were associated with NF-κB activation. Furthermore, LL-37 was shown to bind with ds nucleotides and translocate into cytoplasm. Knockdown of RIG-I decreased expression of CXCL10 induced by LL-37-Poly(I:C) complexes, and RIG-I were co-localized with Poly(I:C) entered by LL-37 in cytoplasm. LL-37 modulates dsRNA-mediated inflammatory response via RIG-I in oral keratinocytes, which may play an important role in the pathogenesis of oral inflammatory diseases.