Utilizing Tajima's D to identify potential microbe-associated molecular patterns in Xanthomonas euvesicatoria and X. perforans

: Glial cells, including microglia and astrocytes, facilitate the survival and health of all cells within the Central Nervous System (CNS) by secreting a range of growth factors and contributing to tissue and synaptic remodeling. Microglia and astrocytes can also secrete cytotoxins in response to specific stimuli, such as exogenous Pathogen-Associated Molecular Patterns (PAMPs), or endogenous Damage-Associated Molecular Patterns (DAMPs). Excessive cytotoxic secretions can induce the death of neurons and contribute to the progression of neurodegenerative disorders, such as Alzheimer’s disease (AD). The transition between various activation states of glia, which include beneficial and detrimental modes, is regulated by endogenous molecules that include DAMPs, cytokines, neurotransmitters, and bioactive lipids, as well as a diverse group of mediators sometimes collectively referred to as Resolution-Associated Molecular Patterns (RAMPs). RAMPs are released by damaged or dying CNS cells into the extracellular space where they can induce signals in autocrine and paracrine fashions by interacting with glial cell receptors. While the complete range of their effects on glia has not been described yet, it is believed that their overall function is to inhibit adverse CNS inflammatory responses, facilitate tissue remodeling and cellular debris removal. This article summarizes the available evidence implicating the following RAMPs in CNS physiological processes and neurodegenerative diseases: cardiolipin (CL), prothymosin α (ProTα), binding immunoglobulin protein (BiP), heat shock protein (HSP) 10, HSP 27, and αB-crystallin. Studies on the molecular mechanisms engaged by RAMPs could identify novel glial targets for development of therapeutic agents that effectively slow down neuroinflammatory disorders including AD.

Download Full-text

Innate Lymphoid Cells (ILCs) Generate Memory for Pathogen-Associated Molecular Patterns (PAMPs) of Allergens, Which Contributes to Asthma

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2018.12.610 ◽

2019 ◽

Vol 143 (2) ◽

pp. AB199

Author(s):

Mukesh Verma ◽

Lidia Michalec ◽

Anand Sripada ◽

Jerome McKay ◽

Kapil Sirohi ◽

...

Keyword(s):

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Molecular Patterns

Download Full-text

Flavonoids Ameliorate Stress-Induced Depression by Preventing NLRP3 Inflammasome Priming

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_047 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1231-1231

Author(s):

Giulio Pasinetti

Keyword(s):

Mrna Expression ◽

Chronic Stress ◽

Nlrp3 Inflammasome ◽

Signaling Cascades ◽

Dietary Polyphenols ◽

Funding Sources ◽

Glycation End Products ◽

Molecular Patterns

Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), stimulating the NLRP3 inflammasome. NLRP3 activation triggers the release of pro-inflammatory cytokine IL-1β. The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. Our previous studies show that polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the relevant mechanism has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US – induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration significantly improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary flavonoids prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of dietary polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH/ODS.

Download Full-text

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 ◽

Damage Associated 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.

Download Full-text

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 ◽

Damage Associated 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.

Download Full-text

Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome

Cancers ◽

10.3390/cancers13112566 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2566

Author(s):

María Julia Lamberti ◽

Annunziata Nigro ◽

Vincenzo Casolaro ◽

Natalia Belén Rumie Vittar ◽

Jessica Dal Col

Keyword(s):

Cell Death ◽

Tumor Cells ◽

Cell Activation ◽

Adaptive Immune Response ◽

Current Status ◽

Immunogenic Cell Death ◽

Basal Expression ◽

Antigen Presenting ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy.

Download Full-text