Role for MyD88-Independent, TRIF Pathway in Lipid A/TLR4-Induced Endotoxin Tolerance

Biswas, Subhra K.; Bist, Pradeep; Dhillon, Manprit Kaur; Kajiji, Tasneem; Fresno, Carlos del; Yamamoto, Masahiro; López‐Collazo, Eduardo; Akira, Shizuo; Tergaonkar, Vinay

doi:10.4049/jimmunol.179.6.4083

Cited by 97 publications

(98 citation statements)

References 55 publications

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“…These results argue against an endotoxin tolerance-like phenomenon, as endotoxin tolerance to the lipid A component of endotoxin has recently been shown to involve down-regulation of MyD88-dependent gene expression, but induction of a TRIF-and IFN␣/␤-dependent pathway. 49 In contrast, we saw an increase in MyD88-dependent cytokines after sepsis following TLR4 or TLR7/8 agonist pretreatment. Our in vivo findings of TLR7/8 agonist pretreatment increasing peritoneal cell phagocytosis correlate with the report by Doyle et al, where in vitro TLR7/8 agonist treatment of RAW 264.7 macrophages was shown to increase phagocytosis via a MyD88-IRAK4-p38-dependent pathway.…”

Section: Discussioncontrasting

confidence: 41%

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Wynn

Scumpia²,

Winfield³

et al. 2008

Blood

159

167

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Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell-directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b ؉ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality. IntroductionSepsis causes profound defects in innate and acquired immunity. In septic adults, circulating leukocytes fail to mount an attenuated inflammatory response, monocytes have defective antigen presentation in part due to reduced MHC class II expression, and dendritic cells and lymphocytes exhibit increased apoptosis. [1][2][3][4] These deficiencies contribute to a failure to clear primary pathogens, an increased propensity to develop superinfections, and an inability to mount adaptive immune responses. Considerable progress has been made in understanding the pathogenesis of and identifying potential immunomodulatory therapies for treating sepsis in adult animals. For example, MyD88 and type I interferon signaling pathways 5,6 are important requisites for innate and inflammatory host defense responses to pathogens. 7,8 Stimulating the innate immune system with Toll-like receptor (TLR) agonists improves survival in adult animal models of sepsis. 9,10 Similarly, absence of the adaptive immune system 11 or an inability of B cells to produce antibodies 12 predisposes adult mice to a poor outcome in sepsis. Correction of adaptive immune dysfunction by prevention of lymphocyte apoptosis or treatment with agonistic glucocorticoid-induced tumor necrosis factor (TNF) receptor antibody (anti-GITR) to stimulate effector T-cell function, improves survival in animal models of adult sepsis. 11,13 These studies highlight the importance of both the innate and adaptive immune systems in eliminating invading pathogens in adult mammals. However, the mechanisms of protective immunity in neonates that do not possess a fully intact immune system, and who develop sepsis at increased rates, 14 are less clear.More than 1 million babies die each year worldwide within the first 4 weeks of life from sepsis. 15 Neonatal sepsis mortality is higher than in children and adults, 16,17 peaking in premature infants, where r...

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Section: Discussioncontrasting

confidence: 41%

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Wynn

Scumpia²,

Winfield³

et al. 2008

Blood

159

167

View full text Add to dashboard Cite

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“…Cross tolerance among different TLRs, which share the MyD88 signaling pathway, has been reported (27)(28)(29). Hence, we tested whether TLR7 agonist pretreatment could induce in vivo tolerance to other TLR agonists.…”

Section: Tlr7-induced Tolerance Resulted In Hyporesponsiveness To Othermentioning

confidence: 99%

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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“…In contrast, the role of the TLR4/TRIF-dependent pathway in endotoxin tolerance and sepsis has not been investigated to a great detail. We have reported a nonredundant role for the TRIF/IFN-b pathway in mediating lipid A (LPA)-induced endotoxin tolerance in mouse embryonal fibroblasts (22). Other observations on the defective expression of classical proinflammatory cytokines such as TNF and IL-1b in TRIF-deficient mice and the fact that the TRIF pathway induces ∼74.4% of the LPS-induced transcriptome in murine macrophages argue for an important role of this pathway in regulating sepsis response at least in the mice (16,17).…”

mentioning

confidence: 99%

CD16 Regulates TRIF-Dependent TLR4 Response in Human Monocytes and Their Subsets

Shalova

Kajiji

Lim

et al. 2012

The Journal of Immunology

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Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16+) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R–associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16+ monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis.

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Role for MyD88-Independent, TRIF Pathway in Lipid A/TLR4-Induced Endotoxin Tolerance

Cited by 97 publications

References 55 publications

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

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

CD16 Regulates TRIF-Dependent TLR4 Response in Human Monocytes and Their Subsets

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