The role of pathogen-associated molecular patterns in inflammatory responses against alginate based microcapsules

Infection continues to be a leading cause of intensive care unit death. The host response to infection can be seen as a pattern recognition receptor (PRR)-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. A measured and rapid response to microbial invasion is essential to health. The same immunological and coagulation systems that protect against localized infection can act to our disadvantage when these systems are activated systemically during generalized microbial infection. Toll-like receptors (TLR), the inflammasomes and other PRRs initiate the host response after recognition of pathogen-associated-molecular-patterns (PAMPs) or endogenous danger-associated-molecular-patterns (DAMPs). The systemic host response to infection will result in activation of coagulation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Further dissection of the role of host–pathogen interactions, the cytokine response, the coagulation cascade and their multidirectional interactions in sepsis should lead towards the development of new therapeutic approaches in the critically ill who are faced with infection.

Download Full-text

The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis

Journal of Immunology Research ◽

10.1155/2019/1824624 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Lixiang Sun ◽

Wenjie Liu ◽

Ling-juan Zhang

Keyword(s):

Atopic Dermatitis ◽

Human Body ◽

Lupus Erythematosus ◽

Mammalian Cells ◽

Skin Diseases ◽

Inflammatory Responses ◽

Innate Immune ◽

Host Responses ◽

Molecular Patterns

As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.

Download Full-text

Innate immune receptors in type 1 diabetes: the relationship to cell death-associated inflammation

Biochemical Society Transactions ◽

10.1042/bst20200131 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1213-1225 ◽

Cited By ~ 1

Author(s):

Tae Kang Kim ◽

Myung-Shik Lee

Keyword(s):

Innate Immunity ◽

Type 1 Diabetes ◽

Inflammatory Responses ◽

Critical Role ◽

Innate Immune ◽

Therapeutic Modalities ◽

Immune Receptors ◽

Molecular Patterns

The importance of innate immunity in host defense and inflammatory responses has been clearly demonstrated after the discovery of innate immune receptors such as Toll-like receptors (TLRs) or Nucleotide-binding oligomerization domain-containing protein (Nod)-like receptors (NLRs). Innate immunity also plays a critical role in diverse pathological conditions including autoimmune diseases such as type 1 diabetes (T1D). In particular, the role of a variety of innate immune receptors in T1D has been demonstrated using mice with targeted disruption of such innate immune receptors. Here, we discuss recent findings showing the role of innate immunity in T1D that were obtained mostly from studies of genetic mouse models of innate immune receptors. In addition, the role of innate immune receptors involved in the pathogenesis of T1D in sensing death-associated molecular patterns (DAMPs) released from dead cells or pathogen-associated molecular patterns (PAMPs) will also be covered. Elucidation of the role of innate immune receptors in T1D and the nature of DAMPs sensed by such receptors may lead to the development of new therapeutic modalities against T1D.

Download Full-text

Caspase-11 regulates lung inflammation in response to house dust mites

10.21203/rs.3.rs-46816/v1 ◽

2020 ◽

Author(s):

Arwa Abu khweek ◽

Marisa R. Joldrichsen ◽

Eunsoo Kim ◽

Zayed Attia ◽

Kathrin Krause ◽

...

Keyword(s):

House Dust ◽

Inflammatory Responses ◽

Allergic Sensitization ◽

Allergic Inflammation ◽

House Dust Mites ◽

Host Responses ◽

Dust Mites ◽

Molecular Patterns

Abstract Asthma is an inflammatory lung disorder characterized by mucus hypersecretion, cellular infiltration, and bronchial hyper-responsiveness. House dust mites (HDM) are the most prevalent cause of allergic sensitization. Canonical and noncanonical inflammasomes are multiprotein complexes that assemble in response to pathogen or danger-associated molecular patterns (PAMPs or DAMPs). Murine caspase-11 engages the noncanonical inflammasome. We addressed the role of caspase-11 in mediating host responses to HDM and subsequent allergic inflammation using caspase-11−/− mice, which lack caspase-11 while express caspase-1. We found that HDM induce caspase-11 expression in vitro. The presence of IL-4 and IL-13 promotes caspase-11 expression. Additionally, caspase-11−/− macrophages show reduced release of (KC, IL-6 and IL-12) cytokines, and express lower levels of costimulatory molecules (e.g., CD40, CD86 and MHCII) in response to HDM stimulation. Notably, HDM sensitization of caspase-11−/− mice resulted in similar levels of IgE responses and hypothermia in response to nasal HDM challenge compared to WT. However, analysis of cell numbers and cytokines in bronchiolar alveolar fluid (BALF), as well as histological lung tissue showed altered inflammatory responses and reduced neutrophilia in the airways of the caspase-11−/− mice. These findings indicate that caspase-11 regulates airway inflammation in response to HDM exposure.

Download Full-text

Inflammasomes in Teleosts: Structures and Mechanisms That Induce Pyroptosis during Bacterial Infection

International Journal of Molecular Sciences ◽

10.3390/ijms22094389 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4389

Author(s):

Natsuki Morimoto ◽

Tomoya Kono ◽

Masahiro Sakai ◽

Jun-ichi Hikima

Keyword(s):

Inflammatory Responses ◽

Current Knowledge ◽

Adaptor Protein ◽

Protective Role ◽

Inflammasome Activation ◽

Multiple Protein ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Oligomerization Domain

Pattern recognition receptors (PRRs) play a crucial role in inducing inflammatory responses; they recognize pathogen-associated molecular patterns, damage-associated molecular patterns, and environmental factors. Nucleotide-binding oligomerization domain-leucine-rich repeat-containing receptors (NLRs) are part of the PRR family; they form a large multiple-protein complex called the inflammasome in the cytosol. In mammals, the inflammasome consists of an NLR, used as a sensor molecule, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as an adaptor protein, and pro-caspase1 (Casp1). Inflammasome activation induces Casp1 activation, promoting the maturation of proinflammatory cytokines, such as interleukin (IL)-1β and IL-18, and the induction of inflammatory cell death called pyroptosis via gasdermin D cleavage in mammals. Inflammasome activation and pyroptosis in mammals play important roles in protecting the host from pathogen infection. Recently, numerous inflammasome-related genes in teleosts have been identified, and their conservation and/or differentiation between their expression in mammals and teleosts have also been elucidated. In this review, we summarize the current knowledge of the molecular structure and machinery of the inflammasomes and the ASC-spec to induce pyroptosis; moreover, we explore the protective role of the inflammasome against pathogenic infection in teleosts.

Download Full-text

Research Progress on the Role of Inflammasomes in Kidney Disease

Mediators of Inflammation ◽

10.1155/2020/8032797 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Kun Chi ◽

Xiaodong Geng ◽

Chao Liu ◽

GuangYan Cai ◽

Quan Hong

Keyword(s):

Kidney Disease ◽

Inflammatory Responses ◽

Kidney Diseases ◽

Interleukin 1 ◽

Research Progress ◽

Chronic Kidney Diseases ◽

Caspase 1 ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Inflammasomes are multimeric complexes composed of cytoplasmic sensors, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC or PYCARD), and procaspase-1 and play roles in regulating caspase-dependent inflammation and cell death. Inflammasomes are assembled by sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and initiate inflammatory responses by activating caspase-1. Activated caspase-1 promotes the release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and eventually induces pyroptosis. Inflammasomes are closely related to kidney diseases. In particular, the NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome has been shown to cause acute and chronic kidney diseases by regulating canonical and noncanonical mechanisms of inflammation. Small-molecule inhibitors that target NLRP3 and other components of the inflammasome are potential options for the treatment of kidney-related diseases such as diabetic nephropathy. This article will focus on the research progress on inflammasomes and the key pathogenic roles of inflammasomes in the development and progression of kidney diseases and explore the potential of this intracellular inflammation to further prevent or block the development of the kidney disease.

Download Full-text

Role of Apoptosis in Amplifying Inflammatory Responses in Lung Diseases

Journal of Cell Death ◽

10.4137/jcd.s5375 ◽

2010 ◽

Vol 3 ◽

pp. JCD.S5375 ◽

Cited By ~ 17

Author(s):

E.P. Schmidt ◽

R.M. Tuder

Keyword(s):

Lung Diseases ◽

Inflammatory Responses ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Disease States ◽

Chronic Lung Diseases ◽

Cellular Environment ◽

Molecular Patterns ◽

Dying Cells

Apoptosis is an important contributor to the pathophysiology of lung diseases such as acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD). Furthermore, the cellular environment of these acute and chronic lung diseases favors the delayed clearance of apoptotic cells. This dysfunctional efferocytosis predisposes to the release of endogenous ligands from dying cells. These so-called damage-associated molecular patterns (DAMPs) play an important role in the stimulation of innate immunity as well as in the induction of adaptive immunity, potentially against autoantigens. In this review, we explore the role of apoptosis in ALI and COPD, with particular attention to the contribution of DAMP release in augmenting the inflammatory response in these disease states.

Download Full-text

The Immunomodulatory Role of G2013 (α-L-Guluronic Acid) on the Expression of TLR2 and TLR4 in HT29 cell line

Current Drug Discovery Technologies ◽

10.2174/1570163815666180226093711 ◽

2019 ◽

Vol 16 (1) ◽

pp. 91-95 ◽

Cited By ~ 4

Author(s):

Hamid Farhang ◽

Laleh Sharifi ◽

Mohammad Mehdi Soltan Dallal ◽

Mona Moshiri ◽

Zahra Norouzbabaie ◽

...

Keyword(s):

Inflammatory Responses ◽

Inflammatory Diseases ◽

Rna Extraction ◽

Cell Plate ◽

Inhibitory Effect ◽

Control Group ◽

Ht29 Cells ◽

Guluronic Acid ◽

Tlr4 Mrna

Background: The non-steroidal anti-inflammatory drugs (NSAIDs) play crucial role in the controlling of inflammatory diseases. Due to the vast side effects of NSAIDs, its use is limited. G2013 or &#945;-L-Guluronic Acid is a new NSAID with immunomodulatory features. Objectives: Considering the leading role of TLRs in inflammatory responses, in this study, we aimed to evaluate G2013 cytotoxicity and its effect on the expression of TLR2 and TLR4 molecules. Methods: HEK293-TLR2 and HEK293-TLR4 cells were cultured and seeded on 96-well cell plate, and MTT assay was performed for detecting the viability of the cells after treatment with different concentrations of G2013. HT29 cells were grown and treated with low and high doses of G2013. After total RNA extraction and cDNA synthesis, quantitative real-time PCR were performed to assess the TLR2 and TLR4 mRNA synthesis. Results: We found that concentrations of ≤125 &#181;g/ml of G2013 had no apparent cytotoxicity effect on the HEK293-TLR2 and -TLR4 cells. Our results indicated that after G2013 treatment (5 &#181;g/ml) in HT29 cells, TLR2 and TLR4 mRNA expression decreased significantly compared with the untreated control group (p=0.02 and p=0.001 respectively). Conclusion: The results of this study revealed that G2013 can down regulate the TLR2 and TLR4 gene expression and exerts its inhibitory effect. Our findings are parallel to our previous finding which showed G2013 ability to down regulate the signaling pathway of TLRs. However, further studies are needed to identify the molecular mechanism of G2013.<p>

Download Full-text

Resolution-Associated Molecular Patterns (RAMPs) as Endogenous Regulators of Glia Functions in Neuroinflammatory Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200702143719 ◽

2020 ◽

Vol 19 (7) ◽

pp. 483-494

Author(s):

Tyler J. Wenzel ◽

Evan Kwong ◽

Ekta Bajwa ◽

Andis Klegeris

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Bioactive Lipids ◽

Prothymosin Α ◽

Neuroinflammatory Disease ◽

Cellular Debris ◽

Αb Crystallin ◽

Endogenous Regulators ◽

The Central Nervous System ◽

Molecular Patterns

: 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

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