scholarly journals NOD-like receptors: major players (and targets) in the interface between innate immunity and cancer

2019 ◽  
Vol 39 (4) ◽  
Author(s):  
Fernando J. Velloso ◽  
Marina Trombetta-Lima ◽  
Valesca Anschau ◽  
Mari C. Sogayar ◽  
Ricardo G. Correa
Keyword(s):  
Innate Immunity ◽  
Tissue Injury ◽  
Large Family ◽  
Nuclear Factor Κb ◽  
Podospora Anserina ◽  
Host Responses ◽  
Interferon Response ◽  
Transcription Activator ◽  
Response Factors ◽  
Molecular Patterns

AbstractInnate immunity comprises several inflammation-related modulatory pathways which receive signals from an array of membrane-bound and cytoplasmic pattern recognition receptors (PRRs). The NLRs (NACHT (NAIP (neuronal apoptosis inhibitor protein), C2TA (MHC class 2 transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein) and Leucine-Rich Repeat (LRR) domain containing proteins) relate to a large family of cytosolic innate receptors, involved in detection of intracellular pathogens and endogenous byproducts of tissue injury. These receptors may recognize pathogen-associated molecular patterns (PAMPs) and/or danger-associated molecular patterns (DAMPs), activating host responses against pathogen infection and cellular stress. NLR-driven downstream signals trigger a number of signaling circuitries, which may either initiate the formation of inflammasomes and/or activate nuclear factor κB (NF-κB), stress kinases, interferon response factors (IRFs), inflammatory caspases and autophagy. Disruption of those signals may lead to a number of pro-inflammatory conditions, eventually promoting the onset of human malignancies. In this review, we describe the structures and functions of the most well-defined NLR proteins and highlight their association and biological impact on a diverse number of cancers.

scholarly journals The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages

2020 ◽  
Vol 5 (51) ◽  
pp. eaaz1974 ◽  
Author(s):  
David M. Calcagno ◽  
Richard P. Ng ◽  
Avinash Toomu ◽  
Claire Zhang ◽  
Kenneth Huang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Steady State ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Transcriptional Regulators ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Molecular Patterns

Sterile tissue injury is thought to locally activate innate immune responses via damage-associated molecular patterns (DAMPs). Whether innate immune pathways are remotely activated remains relatively unexplored. Here, by analyzing ~145,000 single-cell transcriptomes at steady state and after myocardial infarction (MI) in mice and humans, we show that the type I interferon (IFN) response, characterized by expression of IFN-stimulated genes (ISGs), begins far from the site of injury, in neutrophil and monocyte progenitors within the bone marrow. In the peripheral blood of patients, we observed defined subsets of ISG-expressing neutrophils and monocytes. In the bone marrow and blood of mice, ISG expression was detected in neutrophils and monocytes and their progenitors, intensified with maturation at steady-state and after MI, and was controlled by Tet2 and Irf3 transcriptional regulators. Within the infarcted heart, ISG-expressing cells were negatively regulated by Nrf2 activation in Ccr2− steady-state cardiac macrophages. Our results show that IFN signaling begins in the bone marrow, implicate multiple transcriptional regulators (Tet2, Irf3, and Nrf2) in governing ISG expression, and provide a clinical biomarker (ISG score) for studying IFN signaling in patients.

scholarly journals Insight Cross-talk between p53 and Toll-like Receptor

2021 ◽  
pp. 23-29
Author(s):  
Mohammad Jahoor Alam ◽  
Fevzi Bardakci ◽  
Sadia Anjum ◽  
Shumayla Rasheed Mir ◽  
Irfan Ahmad ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Transcription Factors ◽  
Cross Talk ◽  
Experimental Studies ◽  
Therapeutic Interventions ◽  
Toll Like Receptor ◽  
Transcription Activator ◽  
Molecular Patterns ◽  
Broad Understanding

Toll-like receptors (TLR) are one of the most-studied receptors for their role in innate immunity. TLRs are reported to binds with conserved pathogen-associated molecular patterns (PAMPS). TLRs and PAMPS interaction leads to several downstream proteins' activation, which further signaled to the various transcription factors. Moreover, these transcription factors play an important role in synthesizing proteins that control cellular immunity. Various TLR proteins have been reported in humans as well several other organisms. Studies show that apart from inducing innate immunity, TLRs have also played an important role in the induction of many proteins, and protein networks associated with initiation apoptosis and cancer prevention. P53 is one of the most important and widely studied proteins. Moreover, various experimental studies suggest that p53 has an important role as tumor suppressor. It is reported that more than 50% of cancerous growth are associated with the mutation of p53. It acts as transcription activator for several proteins that are mostly associated with glycolysis, cell cycle, cell differentiation, apoptosis and cancer. In the present review, we present an insight cross-talk between p53 and Toll-like receptor. In addition, the well-characterized role of p53 in the regulation of the immune system is studied, which would provide a new insight to the broad understanding of p53 role in human biology. Moreover, the association of the p53 and TLRs can lead to therapeutic interventions.

scholarly journals Increased presence of nuclear DNAJA3 and upregulation of cytosolic STAT1 and of nucleic acid sensors trigger innate immunity in the ClpP-null mouse

Neurogenetics ◽  
2021 ◽  
Author(s):  
Antonia Maletzko ◽  
Jana Key ◽  
Ilka Wittig ◽  
Suzana Gispert ◽  
Gabriele Koepf ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nucleic Acid ◽  
Inflammatory Responses ◽  
Subcellular Fractionation ◽  
Inflammatory Factors ◽  
Null Mouse ◽  
Loss Of Function ◽  
Response Factors ◽  
Perrault Syndrome ◽  
Acid Sensors

AbstractMitochondrial dysfunction may activate innate immunity, e.g. upon abnormal handling of mitochondrial DNA in TFAM mutants or in altered mitophagy. Recent reports showed that also deletion of mitochondrial matrix peptidase ClpP in mice triggers transcriptional upregulation of inflammatory factors. Here, we studied ClpP-null mouse brain at two ages and mouse embryonal fibroblasts, to identify which signaling pathways are responsible, employing mass spectrometry, subcellular fractionation, immunoblots, and reverse transcriptase polymerase chain reaction. Several mitochondrial unfolded protein response factors showed accumulation and altered migration in blue-native gels, prominently the co-chaperone DNAJA3. Its mitochondrial dysregulation increased also its extra-mitochondrial abundance in the nucleus, a relevant observation given that DNAJA3 modulates innate immunity. Similar observations were made for STAT1, a putative DNAJA3 interactor. Elevated expression was observed not only for the transcription factors Stat1/2, but also for two interferon-stimulated genes (Ifi44, Gbp3). Inflammatory responses were strongest for the RLR pattern recognition receptors (Ddx58, Ifih1, Oasl2, Trim25) and several cytosolic nucleic acid sensors (Ifit1, Ifit3, Oas1b, Ifi204, Mnda). The consistent dysregulation of these factors from an early age might influence also human Perrault syndrome, where ClpP loss-of-function leads to early infertility and deafness, with subsequent widespread neurodegeneration.

An arms race: innate antiviral responses and counteracting viral strategies

2007 ◽  
Vol 35 (6) ◽  
pp. 1512-1514 ◽  
Author(s):  
M. Schröder ◽  
A.G. Bowie
Keyword(s):  
Nuclear Factor Κb ◽  
Signalling Pathways ◽  
Type I ◽  
Nuclear Factor ◽  
Regulatory Factor ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Activation Of Transcription ◽  
Molecular Patterns ◽  
Pro Inflammatory Cytokines

Viral recognition is mediated by different classes of PRRs (pattern-recognition receptors) among which the TLRs (Toll-like receptors) and the RLHs [RIG (retinoic-acid-inducible)-like helicases] play major roles. The detection of PAMPs (pathogen-associated molecular patterns) by these PRRs leads to the initiation of signalling pathways that ultimately result in the activation of transcription factors such as NF-κB (nuclear factor κB) and IRF-3 [IFN (interferon) regulatory factor-3] and IRF-7 and the induction of pro-inflammatory cytokines and type I IFNs. Viruses have evolved a fine-tuned mechanism to evade detection by the immune system or to interfere with the resulting signalling pathways. Here, we discuss viral evasion proteins that specifically interfere with TLR and/or RLH signalling.

scholarly journals Image-recognizing receptors of the innate immunity and their role in immunotherapy (review)

2020 ◽  
pp. 4-15
Author(s):  
О.Ю. Филатов ◽  
В.А. Назаров
Keyword(s):  
Innate Immunity ◽  
Membrane Surface ◽  
Immune Defense ◽  
Molecular Structures ◽  
Membrane Receptors ◽  
Toll Like Receptors ◽  
Lectin Receptors ◽  
Wide Range ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Данная статья обобщает накопившуюся на сегодняшний день информацию о многообразии образраспознающих рецепторов, их роли в регуляции иммунной системы. Распознавание патогена врожденным иммунитетом происходит с помощью рецепторов к широкому спектру антигенов за счет выделения нескольких высоко консервативных структур микроорганизмов. Эти структуры были названы патоген-ассоциированные образы (Patogen-Associated Molecular Patterns - PAMP). Наиболее изученными являются липополисахарид грамм отрицательных бактерий (LPS), липотейхоевые кислоты, пептидогликан (PGN), CpG мотивы ДНК и РНК. Рецепторы, распознающие PAMP, называются PRR. Данная группа рецепторов также распознает молекулы, образующиеся при повреждении собственных тканей. Такие молекулярные структуры называются Damage-Associated Molecular Patterns (DAMP), или образы, ассоциированные с повреждением. В качестве DAMP могут выступать белки теплового шока, хроматин, фрагменты ДНК. В зависимости от локализации, образраспознающие рецепторы принято разделять на: расположенные на мембране Toll-подобные рецепторы (Toll-like receptors, TLR) и рецепторы лектина С-типа (C-type lectin receptors, CLR), а также расположенные в цитоплазме NOD-подобные рецепторы (NOD-like receptors, NLR) и цитоплазматические РНК- и ДНК-сенсоры. Сегодня у человека известно 10 типов TLR, часть из которых расположена на поверхности (TLR1-TLR6, TLR10) большинства клеток, в том числе макрофагов, В-лимфоцитов и дендритных клеток, а часть - в эндосомах (TLR3, TLR7-TLR9). CLR представляет из себя семейство рецепторов, расположенных на мембране и имеющих домены распознавания углеводов (CRD), или структурно сходные лектиноподобные домены типа C (CTLD). В данном семействе рецепторов принято по происхождению и структуре выделять 17 групп. CLR активно участвуют в противогрибковой иммунной защите, а также они играют роль в защите и от других типов микроорганизмов. NOD (нуклеотидсвязывающий и олигомеризационный домен)-подобные рецепторы расположены в цитоплазме. Благодаря этим рецепторам, патоген, который избежал распознавания на поверхности мембраны, сталкивается со вторым уровнем распознавания уже внутри клетки. В данной статье рассматриваются пути активации образраспознающих рецепторов, их эффекты и применение данных эффектов в медицине. This article summarizes currently available information about the variety of image-recognizing receptors and their role in regulation of the immune system. Pathogen recognition by the innate immunity is mediated by receptors to a wide range of antigens via recognition of several highly conservative structures of microorganisms. These structures were named pathogen-associated images or PAMP (pathogen-associated molecular pattern). The best studied types of such structures include lipopolysaccharide (LPS) of gram-negative bacteria, lipoteichoic acids, peptidoglycan (PGN), and CpG DNA and RNA motifs. PAMP-recognizing receptors (PRRS) are a group of receptors, which also recognize molecules released during damage of host tissues. Such molecular structures are called DAMPS (damage-associated molecular patterns) or damage-associated images. Heat shock proteins, chromatin, and DNA fragments may act as DAMPS. Depending on the localization, image-recognizing receptors are generally classified as membrane-located Toll-like receptors (TLR) and C-type lectin receptors (CLR), as well as cytoplasmic NOD-like receptors (NLR) and cytoplasmic RNA and DNA sensors. Today, 10 types of human TLR are known. Some of them are located on the surface (TLR1-TLR6, TLR10) of most cells, including macrophages, B-cells, and dendritic cells, and some are present in endosomes (TLR3, TLR7-TLR9). CLR is a family of membrane receptors that have carbohydrate recognition domains (CRD) or structurally similar lectin-like type C domains (CTLD). Seventeen groups are distinguished within this receptor family based on their origin and structure. CLRs are actively involved in antifungal immune defense and also play a role in protection against other types of microorganisms. NOD (nucleotide-binding and oligomerization domain)-like receptors are present in the cytoplasm. These receptors provide the second level of recognition inside the cell for the pathogens that have escaped recognition on the membrane surface. This article discusses activation pathways of image-recognizing receptors, their effects, and the use of such effects in medicine.

scholarly journals Type I interferon responses to ischemic injury begin in the bone marrow of mice and humans and depend on Tet2, Nrf2, and Irf3

2019 ◽  
Author(s):  
David M. Calcagno ◽  
Richard P. Ng ◽  
Avinash Toomu ◽  
Claire Zhang ◽  
Kenneth Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Type I Interferon ◽  
Tissue Injury ◽  
Type I ◽  
Blood Neutrophils ◽  
Clinical Biomarker ◽  
Acute Mi ◽  
Molecular Patterns ◽  
Interferon Responses ◽  
Myeloid Progenitors

AbstractSterile tissue injury locally activates innate immune responses via interactions with damage associated molecular patterns (DAMPs). Here, by analyzing ∼120K single cell transcriptomes after myocardial infarction (MI) in mice and humans, we show neutrophil and monocyte subsets induce type I interferon (IFN) stimulated genes (ISGs) in myeloid progenitors of the bone marrow, far from the site of injury. In patients with acute MI, peripheral blood neutrophils and monocytes express ISGs at levels far beyond healthy individuals and comparable to patients with lupus. In the bone marrow of Tet2-/- mice, ISGs are spontaneously induced in myeloid progenitors and their progeny. In the heart, IFN responses are negatively regulated by Ccr2- resident macrophages in a Nrf2-dependent fashion. Our results show post-MI IFN signaling begins in the bone marrow, implicate multiple transcription factors in its regulation (Tet2, Irf3, Nrf2), and provide a clinical biomarker (ISG score) for studying post-MI IFN signaling in patients.

scholarly journals The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Monica Molteni ◽  
Sabrina Gemma ◽  
Carlo Rossetti
Keyword(s):  
Tissue Injury ◽  
Sterile Inflammation ◽  
Research Progress ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
The Family ◽  
Tlr4 Activation ◽  
Molecular Patterns

Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions.

2007 George L. Duff Memorial Lecture—The Immune Response in Atherosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Göran K. Hansson
Keyword(s):  
Innate Immunity ◽  
Vascular Inflammation ◽  
Experimental Studies ◽  
Memorial Lecture ◽  
Immune Reactions ◽  
Specific Antigens ◽  
Atherosclerotic Process ◽  
Molecular Patterns ◽  
Lipoprotein Retention

Immune responses participate in every phase of atherosclerosis. Indeed, atherosclerosis can be viewed as an immune/inflammatory response to lipoprotein retention in the artery wall. There is increasing evidence that both adaptive and innate immunity tightly regulate the atherosclerotic process. Specific antigens and pathogen-like molecular patterns initiate the 2 aspects of immunity by ligating T- and B-cell receptors and pattern recognition receptors, respectively. Effector responses of vascular immune reactions include macrophage activation, cellular immunity, antibody formation, and vascular inflammation. Whereas experimental studies in gene-targeted models have identified major roles for innate immunity and Th1 responses in plaque initiation and progression, clinical, epidemiological and genetic studies suggest that plaque activation, rupture, and atherothrombosis also depend on immune reactions. This lecture will focus on the role of immune mechanisms in the formation and activation of atherosclerotic plaques.

Sign in / Sign up

Export Citation Format

Share Document