Abstract 904: Heterozygous ATG7 inhibition enhances endocrine therapy responsiveness through regulation of damage associated molecular patterns and priming the immune system in ER+ breast tumors

How does the immune system know when to respond? ‘First responders: the innate immune response’ considers this fundamental question that is central to understanding both normal (e.g. to infections) and abnormal (e.g. in auto-immune diseases) responses; and designing vaccines and new therapies in cancer and infectious diseases. It looks at how ‘danger’ is sensed by the immune system through pathogen-associated molecular patterns and damage-associated molecular patterns. Having been alerted, it is important that rapid action is taken to limit the spread of a pathogen. A number of responses can be initiated immediately, forming a critical part of our innate immunity, which are followed by the acute phase response.

Inhibitory pattern recognition receptors

Journal of Experimental Medicine ◽

10.1084/jem.20211463 ◽

2021 ◽

Vol 219 (1) ◽

Author(s):

Matevž Rumpret ◽

Helen J. von Richthofen ◽

Victor Peperzak ◽

Linde Meyaard

Keyword(s):

Pattern Recognition ◽

Cell Death ◽

Immune System ◽

Immune Responses ◽

Pattern Recognition Receptors ◽

Inhibitory Receptors ◽

Danger Signals ◽

Molecular Pattern ◽

Molecular Patterns ◽

Pathogen- and damage-associated molecular patterns are sensed by the immune system’s pattern recognition receptors (PRRs) upon contact with a microbe or damaged tissue. In situations such as contact with commensals or during physiological cell death, the immune system should not respond to these patterns. Hence, immune responses need to be context dependent, but it is not clear how context for molecular pattern recognition is provided. We discuss inhibitory receptors as potential counterparts to activating pattern recognition receptors. We propose a group of inhibitory pattern recognition receptors (iPRRs) that recognize endogenous and microbial patterns associated with danger, homeostasis, or both. We propose that recognition of molecular patterns by iPRRs provides context, helps mediate tolerance to microbes, and helps balance responses to danger signals.

Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00328.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. H184-H196 ◽

Cited By ~ 105

Author(s):

Cameron G. McCarthy ◽

Styliani Goulopoulou ◽

Camilla F. Wenceslau ◽

Kathryn Spitler ◽

Takayuki Matsumoto ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Cell Injury ◽

Receptor Activation ◽

Innate Immune ◽

Immune System Activation ◽

System Activation ◽

Molecular Patterns ◽

Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.

DAMPening Inflammation by Modulating TLR Signalling

Mediators of Inflammation ◽

10.1155/2010/672395 ◽

2010 ◽

Vol 2010 ◽

pp. 1-21 ◽

Cited By ~ 452

Author(s):

A. M. Piccinini ◽

K. S. Midwood

Keyword(s):

Immune System ◽

Tissue Damage ◽

Tissue Repair ◽

Inflammatory Responses ◽

Current Knowledge ◽

Feedback Loops ◽

Inflammatory Gene Expression ◽

Molecular Patterns ◽

Tlr Signalling

Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

Scavenging nucleic acid debris to combat autoimmunity and infectious disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1607011113 ◽

2016 ◽

Vol 113 (35) ◽

pp. 9728-9733 ◽

Cited By ~ 20

Author(s):

Eda K. Holl ◽

Kara L. Shumansky ◽

Luke B. Borst ◽

Angela D. Burnette ◽

Christopher J. Sample ◽

...

Keyword(s):

Immune System ◽

Nucleic Acid ◽

Innate Immune ◽

Nucleic Acid Binding ◽

Downstream Effector ◽

Wide Range ◽

Molecular Patterns ◽

Dying Cells ◽

Lethal Doses

Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal’s ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.

DAMPs and Innate Immune Training

Frontiers in Immunology ◽

10.3389/fimmu.2021.699563 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elisa Jentho ◽

Sebastian Weis

Keyword(s):

Immune System ◽

Adaptive Immune System ◽

Innate Immune ◽

Immune Memory ◽

Trained Immunity ◽

Downstream Signaling ◽

Adaptive Immune ◽

Open Questions ◽

Molecular Patterns ◽

The ability to remember a previous encounter with pathogens was long thought to be a key feature of the adaptive immune system enabling the host to mount a faster, more specific and more effective immune response upon the reencounter, reducing the severity of infectious diseases. Over the last 15 years, an increasing amount of evidence has accumulated showing that the innate immune system also has features of a memory. In contrast to the memory of adaptive immunity, innate immune memory is mediated by restructuration of the active chromatin landscape and imprinted by persisting adaptations of myelopoiesis. While originally described to occur in response to pathogen-associated molecular patterns, recent data indicate that host-derived damage-associated molecular patterns, i.e. alarmins, can also induce an innate immune memory. Potentially this is mediated by the same pattern recognition receptors and downstream signaling transduction pathways responsible for pathogen-associated innate immune training. Here, we summarize the available experimental data underlying innate immune memory in response to damage-associated molecular patterns. Further, we expound that trained immunity is a general component of innate immunity and outline several open questions for the rising field of pathogen-independent trained immunity.

Mitochondria-Derived Damage-Associated Molecular Patterns in Sepsis: From Bench to Bedside

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6914849 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Sicheng Li ◽

Qiongyuan Hu ◽

Jinjian Huang ◽

Xiuwen Wu ◽

Jianan Ren

Keyword(s):

Immune System ◽

Signaling Pathways ◽

Clinical Importance ◽

Health Hazards ◽

Life And Death ◽

Metabolic Functions ◽

Molecular Patterns ◽

In Cells

Sepsis is one of the most serious health hazards. Current research suggests that the pathogenesis of sepsis is mediated by both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Mitochondria are among the most important organelles in cells and determine their life and death. A variety of mitochondria-derived DAMPs (mtDAMPs) are similar to bacteria because mitochondria are derived from bacteria according to the mitochondrial endosymbiotic theory. Their activated signaling pathways extensively affect organ functions, the immune system, and metabolic functions in sepsis. In this review, we describe the essential roles of mtDAMPs in sepsis and discuss their research prospects and clinical importance.

Faculty Opinions recommendation of Plant immunity triggered by engineered in vivo release of oligogalacturonides, damage-associated molecular patterns.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725433551.793505840 ◽

2015 ◽

Author(s):

Keith Davis

Keyword(s):

Plant Immunity ◽

In Vivo Release ◽

Molecular Patterns ◽

Release mechanisms of major DAMPs

APOPTOSIS ◽

10.1007/s10495-021-01663-3 ◽

2021 ◽

Vol 26 (3-4) ◽

pp. 152-162

Author(s):

Atsushi Murao ◽

Monowar Aziz ◽

Haichao Wang ◽

Max Brenner ◽

Ping Wang

Keyword(s):

Rna Binding ◽

High Mobility ◽

Live Cells ◽

Membrane Channel ◽

Membrane Rupture ◽

Underlying Mechanisms ◽

Shock Proteins ◽

Molecular Patterns ◽

Secretory Lysosomes

AbstractDamage-associated molecular patterns (DAMPs) are endogenous molecules which foment inflammation and are associated with disorders in sepsis and cancer. Thus, therapeutically targeting DAMPs has potential to provide novel and effective treatments. When establishing anti-DAMP strategies, it is important not only to focus on the DAMPs as inflammatory mediators but also to take into account the underlying mechanisms of their release from cells and tissues. DAMPs can be released passively by membrane rupture due to necrosis/necroptosis, although the mechanisms of release appear to differ between the DAMPs. Other types of cell death, such as apoptosis, pyroptosis, ferroptosis and NETosis, can also contribute to DAMP release. In addition, some DAMPs can be exported actively from live cells by exocytosis of secretory lysosomes or exosomes, ectosomes, and activation of cell membrane channel pores. Here we review the shared and DAMP-specific mechanisms reported in the literature for high mobility group box 1, ATP, extracellular cold-inducible RNA-binding protein, histones, heat shock proteins, extracellular RNAs and cell-free DNA.

Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs

Nature Communications ◽

10.1038/s41467-021-21984-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kiran Todkar ◽

Lilia Chikhi ◽

Véronique Desjardins ◽

Firas El-Mortada ◽

Geneviève Pépin ◽

...

Keyword(s):

Extracellular Vesicles ◽

Mitochondrial Proteins ◽

Control Mechanisms ◽

Mitochondrial Content ◽

Sorting Nexin ◽

Inflammatory Conditions ◽

Selective Targeting ◽

Molecular Patterns ◽

Insight Into

AbstractMost cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson’s disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.