Toll-Like Receptor (TLR) Response Tolerance: A Key Physiological “ Damage Limitation ” Effect and an Important Potential Opportunity for Therapy

Broad, Andrea; Jones, David; Kirby, John A.

doi:10.2174/092986706778201675

Cited by 79 publications

(63 citation statements)

References 209 publications

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“…Classically, low doses of the TLR4 agonist LPS, desensitize the host to subsequent endotoxin stimulation, a phenomenon known as endotoxin tolerance (11,12). This desensitization property has been described with other TLR agonists (13) and will be referred to as tolerance in this study.…”

mentioning

confidence: 76%

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Hayashi¹,

Gray²,

Chan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.arthritis ͉ encephalomyelitis ͉ synthetic agonist

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mentioning

confidence: 76%

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Hayashi¹,

Gray²,

Chan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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“…Although the underlying mechanisms implicated in ET have been extensively studied, including reprogrammed epigenetic, microRNAs, and several molecules (1,7,27,28), a complete picture of this process is still lacking. In-depth studies of ET have analyzed the participation of a number of factors and have established the role of several negative regulators, such as IRAK-M, ST2, suppressor of cytokine signaling 1, short version of MyD88 and SHIP, as well as the dysregulation of TLR4 and TREM-1 (4,12,29,30), roles that have been observed occasionally in different models (1,9).…”

Section: Discussionmentioning

confidence: 99%

NFκB2/p100 Is a Key Factor for Endotoxin Tolerance in Human Monocytes: A Demonstration Using Primary Human Monocytes from Patients with Sepsis

Cubillos‐Zapata

Hernández-Jiménez

Toledano

et al. 2014

The Journal of Immunology

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Endotoxin tolerance (ET) is a state of reduced responsiveness to endotoxin stimulation after a primary bacterial insult. This phenomenon has been described in several pathologies, including sepsis, in which an endotoxin challenge results in reduced cytokine production. In this study, we show that the NFκ L chain enhancer of activated B cells 2 (NFκB2)/p100 was overexpressed and accumulated in a well-established in vitro human monocyte model of ET. The p100 accumulation in these cells inversely correlated with the inflammatory response after LPS stimulation. Knocking down NFκB2/p100 using small interfering RNA in human monocytes further indicated that p100 expression is a crucial factor in the progression of ET. The monocytes derived from patients with sepsis had high levels of p100, and a downregulation of NFκB2/p100 in these septic monocytes reversed their ET status.

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“…These include a possible role for TAM-receptor-mediated inhibition of endotoxin tolerance and immune suppression -phenomena in which hypo-responsiveness to TLR engagement is induced by prior TLR activation 83,84 . In macrophages, components of the TAM pathway that are upregulated during inflammation must turn over with a half-life that allows responding cells to return to their baseline levels.…”

Section: Prospects and Implicationsmentioning

confidence: 99%

Immunobiology of the TAM receptors

2008

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Recent studies have revealed that the TAM receptor protein tyrosine kinases -TYRO3, AXL and MER -have pivotal roles in innate immunity. They inhibit inflammation in dendritic cells and macrophages, promote the phagocytosis of apoptotic cells and membranous organelles, and stimulate the maturation of natural killer cells. Each of these phenomena may depend on a cooperative interaction between TAM receptor and cytokine receptor signalling systems. Although its importance was previously unrecognized, TAM signalling promises to have an increasingly prominent role in studies of innate immune regulation.Receptor protein tyrosine kinases (PTKs) are cell-surface transmembrane receptors that contain a regulated PTK activity within their cytoplasmic domains. They function as sensors for extracellular ligands, the binding of which triggers receptor dimerization and activation of the receptor's kinase. This leads to the recruitment, phosphorylation and activation of multiple downstream signalling proteins, which ultimately change the physiology of cells. Although there are only 58 receptor PTK genes in the human genome 1 (see the human kinome website), the signal transduction cascades initiated by receptor PTK activation control diverse cellular processes -from cell differentiation to cell death. Well-known receptor PTK subfamilies include the ERBB receptors, which have essential roles in cardiac and neural development and the progression of some forms of breast cancer 2 ; and the ephrin receptors, which are required for tissue morphogenesis and the patterning of neuronal connections in the developing brain 3 .The focus of this Review, the TAM group, was among the last receptor PTK subfamilies to be identified, and the biological roles of its three members -TYRO3, AXL and MERremained uncharacterized for several years. Largely through the analysis of engineered lossof-function mutants in mice, these roles have become increasingly apparent. They reflect a specific requirement for TAM signalling in settings in which fully differentiated cells, tissues and organs must be maintained in the face of continuous challenge, turnover and renewal. In humans, ongoing homeostatic regulation of this sort must be carried out, frequently on a daily basis, for decades. Although an essential role for TAM regulation of tissue homeostasis is evident in the adult nervous, reproductive and vascular systems, it is in In this Review, we highlight the central roles that TAM signalling has in the intrinsic inhibition of the inflammatory response to pathogens by dendritic cells (DCs) and macrophages; during phagocytosis of apoptotic cells by these same cells; and in the maturation and killing activity of natural killer (NK) cells. We also discuss how, in many or all of these settings, TAM receptors depend on and interact with cytokine receptors. TAM receptors and ligandsThe three TAM receptors, TYRO3, AXL and MER, were identified as a distinct receptor PTK subfamily in 1991 (REFS 4,5 ). Subsequent cloning of full-length cDNAs by multiple labo...

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Toll-Like Receptor (TLR) Response Tolerance: A Key Physiological “ Damage Limitation ” Effect and an Important Potential Opportunity for Therapy

Cited by 79 publications

References 209 publications

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

NFκB2/p100 Is a Key Factor for Endotoxin Tolerance in Human Monocytes: A Demonstration Using Primary Human Monocytes from Patients with Sepsis

Immunobiology of the TAM receptors

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