Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders

Fukata, Masayuki; Vamadevan, Arunan S.; Abreu, María T.

doi:10.1016/j.smim.2009.06.005

Cited by 280 publications

(227 citation statements)

References 216 publications

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“…This concept is especially intriguing, because substances from bacteria, fungi, or viruses generally known as 'pathogen-associated molecular patterns' (PAMP) can directly bind to pathogen recognition receptors (PRR) leading to cell activation and immune modulation without the need of previous sensitization (66,67). It is well established that mast cells and basophils express PRR and are activated by different PAMP (68,69), which could alter their responsiveness (70). Indeed, it was shown that the PAMP peptidoglycan (PGN) can induce degranulation in human (71) and murine mast cells (72).…”

Section: Infections As Cofactors Of Anaphylaxismentioning

confidence: 99%

About the role and underlying mechanisms of cofactors in anaphylaxis

Wölbing

Fischer

Köberle

et al. 2013

Allergy

178

163

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Anaphylaxis is the systemic and most severe presentation of type I allergy. A number of conditions were identified that modulate the onset of anaphylaxis such as co-or augmentation factors, which significantly lower the allergen dose necessary for triggering anaphylaxis. Next to physical exercise or alcohol consumption, co-administration of nonsteroidal anti-inflammatory drugs (NSAID) or concomitant infectious diseases are well-documented cofactors of anaphylaxis. Registries for anaphylaxis document a role for cofactors in about 30% of anaphylactic reactions. Some disease entities such as 'wheat-dependent exercise-induced anaphylaxis' (WDEIA) are explicitly characterized by elicitation of anaphylaxis only in the presence of at least one such cofactor. Using WDEIA as a model disease, studies demonstrated that exercise increases skin prick test reactivity to and bioavailability of the allergen. Additional data indicate that alcohol consumption and NSAID administration display similar effects. Modulation of the cellular activation threshold is another mechanism underlying cofactor-induced anaphylaxis, most likely also functional when infectious diseases orchestrate elicitation of anaphylaxis. Cofactors are increasingly accepted to play a fundamental role in eliciting anaphylaxis. Consequently, to improve patient management modalities, a better understanding of the underlying mechanisms is warranted. This review aims to update clinicians and clinical scientists on recent developments.

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Section: Infections As Cofactors Of Anaphylaxismentioning

confidence: 99%

About the role and underlying mechanisms of cofactors in anaphylaxis

Wölbing

Fischer

Köberle

et al. 2013

Allergy

178

163

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“…Excessive immune responses are detrimental to the host, and thus proper regulation of immune responses is critical for maintaining immune homeostasis and preventing inflammatory disorders and septic shock (35). Following recent rapid advances in the field of innate immunity, innate immune receptors have become attractive targets in the development of anti-inflammatory drugs (53).…”

Section: Discussionmentioning

confidence: 99%

“…Maturation and secretion of TNF-␣ are dependent on cleavage by TNF-␣-converting enzyme (TACE) (33). A substantial amount of TNF-␣ precursor remains uncleaved and is degraded through the lysosomal pathway (34 sis and/or release of pro-inflammatory mediators are tightly controlled, dysregulation or overproduction of these mediators may cause septic shock or other inflammatory disorders (35). Studies using animal models have revealed that TLRs play an important role in the pathogenesis of chronic inflammatory disease such as lupus, experimental autoimmune encephalomyelitis, and chronic colitis (36 -42).…”

mentioning

confidence: 99%

A Novel Aminosaccharide Compound Blocks Immune Responses by Toll-like Receptors and Nucleotide-binding Domain, Leucine-rich Repeat Proteins

Lee

Liu

Biswas

et al. 2011

Journal of Biological Chemistry

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Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat (NLR) proteins are two major forms of innate immune receptors that trigger inflammatory responses by various biological mechanisms such as cytokine production, recruitment of inflammatory cells, or activation of adaptive immunity. Although the innate immune system is designed to fight against infectious pathogens, excessive activation of TLR or NLR signaling pathways may lead to unwarranted inflammation with hazardous outcomes, including septic shock or inflammatory diseases. As part of the search for effective therapeutics to regulate these responses, here we show that a novel aminosaccharide compound, named DFK1012, inhibits immune responses caused by TLR and NLR activation. Treatment with DFK1012, but not its derivatives DFK845 or DFK846, strongly inhibited pro-inflammatory cytokine production upon stimulation via either TLR or NLR proteins in macrophages. Importantly, we have not observed cytotoxicity in any range of its working concentration. Treatment with DFK1012 did not interfere with TLR-or NLR-induced activation of p38 and JNK, phosphorylation/degradation of IB, and subsequent nuclear translocation of NF-B subunit p65, suggesting that the inhibitory activity of DFK1012 is not due to the suppression of downstream signaling. Indeed, DFK1012 did not impair transcription of pro-inflammatory cytokine genes but rather promoted post-translational degradation of pro-inflammatory cytokines. Therefore, DFK1012 is a novel anti-inflammatory compound that drives proteolysis of proinflammatory cytokines induced by TLR and NLR stimulation. DFK1012 may represent a novel class of potential therapeutic agents aimed at the treatment of inflammatory disorders.The innate immune system serves as the first line of host defense against infectious agents by detecting the presence of microbial infection through germ line-encoded pattern recognition receptors (1). Membrane-bound Toll-like receptors (TLRs) 2 as well as cytoplasmic nucleotide-binding domain and leucine-rich repeat (NBD-LRRs or NLRs) protein families are important groups of pattern recognition receptors that provide immediate immune responses by recognizing different but overlapping microbial components, frequently referred to as pathogen-associated molecular patterns (PAMPs) (2). Mammalian TLRs detect components from various microorganisms, including bacteria, viruses, and protozoa (3-18). Signaling of TLRs utilizes an adaptor MyD88, except for TLR3, which requires an adaptor TIR-domain-containing adapter-inducing interferon-␤ (TRIF), leading to the activation of signaling cascades such as MAP kinases and NF-B. These events result in the transcriptional activation of immune response genes and lead to the up-regulation of surface co-stimulatory molecules on antigen-presenting cells and the secretion of pro-inflammatory cytokines such as IL-6, IL-8, .Similar to TLRs, NLR proteins have been shown to play an important role in the recognition and control of bacterial infection (23,24). For ex...

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“…Adenosine triphosphate (ATP), heat shock pro-teins, hyaluronan, monosodium urate, galectins, adenosine, high-mobility group box protein 1 (HMGB1), IL-1α, and IL-33 have been identi ed as DAMPs [12]. DAMPs are sensed through a cytosolic in ammasome complex, which is formed by NLR (nucleotide-binding domain and leucine-rich repeat containing family), ASC (apoptosis-associated speck like protein containing a caspase recruitment domain), and pro-caspase-1 in the cytoplasm [13,14]. Activation of the in ammasome complex leads to subsequent activation of proin ammatory cytokines such as IL-1β and IL-18 [13].…”

Section: Epidermismentioning

confidence: 99%

Novel insights into the role of immune cells in skin and inducible skin-associated lymphoid tissue (iSALT)

Ono¹,

Kabashima²

2015

Allergo J

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Summarye skin is equipped with serial barriers that provide rapid and e cient protection against external intruders. Beneath the epidermal physical barriers of the stratum corneum and the tight junctions, the integrated immune systems in both the epidermis and the dermis act in a coordinated manner to protect the host.is "immunological" barrier is composed of various cells, including skin-resident cells, such as keratinocytes, dendritic cells, tissue-resident macrophages, resident memory T cells, mast cells, and innate lymphoid cells. Additionally, in ltrating memory T cells, monocytes, neutrophils, basophils, and eosinophils are recruited in support of the host immunity.In addition to discussing the role of each of these cellular populations, we describe the concept of skin associated lymphoid tissue (SALT), which reminds us that the skin is an important component of the lymphatic system. We further describe the newly discovered phenomenon of multiple cell gathering under skin in ammation, which can be referred to as inducible SALT (iSALT). iSALT contributes to our understanding of SALT by highlighting the importance of direct cell-cell interaction in skin immunity.Cite this as Ono S, Kabashima K. Novel insights into the role of immune cells in skin and inducible skin-associated lymphoid tissue (iSALT). Allergo J Int 2015;24:170-9

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Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders

Cited by 280 publications

References 216 publications

About the role and underlying mechanisms of cofactors in anaphylaxis

About the role and underlying mechanisms of cofactors in anaphylaxis

A Novel Aminosaccharide Compound Blocks Immune Responses by Toll-like Receptors and Nucleotide-binding Domain, Leucine-rich Repeat Proteins

Novel insights into the role of immune cells in skin and inducible skin-associated lymphoid tissue (iSALT)

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