Cutting Edge: Endotoxin Tolerance in Mouse Peritoneal Macrophages Correlates with Down-Regulation of Surface Toll-Like Receptor 4 Expression

Nomura, Fumiko; Akashi, Shigeo; Sakao, Yoshimitsu; Sato, Shintaro; Kawai, Taro; Matsumoto, Makoto; Nakanishi, Kenji; Kimoto, Masao; Miyake, Kensuke; Takeda, Kiyoshi; Akira, Shizuo

doi:10.4049/jimmunol.164.7.3476

Cited by 693 publications

(593 citation statements)

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“…However, the degree of LPS tolerance is reportedly dependent on the timing of LPS injection. 14 In separate experiments, the 'challenge' dose of LPS was given 6 h (not 24 h) after the 'inducing' LPS dose at which time tolerance was only detected in p53 − / − animals (Supplementary Figure S7B). Thus, depending on the experimental circumstances, loss of p53 predisposes to the development of LPS tolerance.…”

Section: Resultsmentioning

confidence: 99%

A unique role for p53 in the regulation of M2 macrophage polarization

Li¹,

et al. 2014

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P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function. Macrophages have key roles in the response to stress, injury, infection and inflammation. The M1 (classically activated macrophages) are induced by lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFNγ) and characterized by the expression of a wide range of proinflammatory genes. M2 (alternatively activated macrophages) are induced by T helper type 2 (Th2) cytokines such as interleukin-4 (IL4) and IL13 and express high levels of anti-inflammatory and tissue repair marker genes. M2 macrophages perform immunoregulatory functions including defense against infection, promotion of angiogenesis and wound healing. 1 Macrophages exist on a continuum between M1 and M2 subtypes undergoing dynamic changes between these different functional states depending on changes in their microenvironment. This 'plasticity' involves extensive changes in macrophage gene sets and provides the potential to develop drugs to manipulate the macrophage subtype. 2 As such, macrophage polarization, and its molecular basis, has been vigorously researched in recent years.P53 has a crucial role in cancer by controlling the expression of genes involved in apoptosis, cell cycle arrest, metabolism and DNA repair. 3 While inflammation is increasingly recognized as a factor in determining the predisposition to cancer, 4 the role of p53 in inflammation is not clear. Macrophages from p53 − / − mice produce increased quantities of proinflammatory cytokines in response to LPS, 5 while peritoneal macrophage count and susceptibility to lethal septic shock are increased in p53 − ...

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Section: Resultsmentioning

confidence: 99%

A unique role for p53 in the regulation of M2 macrophage polarization

Li¹,

et al. 2014

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“…Most recently RelB inhibitor‐treated autologous DC have shown efficacy in a Phase 1 clinical trial of patients with rheumatoid arthritis 13. Interestingly, although most of the studies investigating ET have been in vitro studies in which macrophages,39, 75 and less so DC,35 are refractory to a second challenge with LPS (“homotolerance”) a few studies have shown that macrophages pre‐exposed to one TLR‐agonist become unresponsive to challenge with another TLR‐agonist (“heterotolerance”). For instance, LPS‐primed macrophages fail to respond to a second challenge with extracts from other Gram‐negative bacteria 37, 64, 76.…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

et al. 2016

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SummaryExposure of bone‐marrow‐derived dendritic cells (BMDC) to high‐dose ultrapure lipopolysaccharide for 24 hr (LPS‐primed BMDC) enhances their potency in preventing inter‐photoreceptor retinoid binding protein: complete Freund's adjuvant‐induced experimental autoimmune uveoretinitis (EAU). LPS‐primed BMDC are refractory to further exposure to LPS (= endotoxin tolerance), evidenced here by decreased phosphorylation of TANK‐binding kinase 1, interferon regulatory factor 3 (IRF3), c‐Jun N‐terminal kinase and p38 mitogen‐activated protein kinase as well as impaired nuclear translocation of nuclear factor κB (NF‐κB) and IRF3, resulting in reduced tumour necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), IL‐12 and interferon‐β secretion. LPS‐primed BMDC also show reduced surface expression of Toll‐like receptor‐4 and up‐regulation of CD14, followed by increased apoptosis, mediated via nuclear factor of activated T cells (NFATc)‐2 signalling. LPS‐primed BMDC are not only homotolerant to LPS but are heterotolerant to alternative pathogen‐associated molecular pattern ligands, such as mycobacterial protein extract (Mycobacterium tuberculosis). Specifically, while M. tuberculosis protein extract induces secretion of IL‐1β, TNF‐α and IL‐6 in unprimed BMDC, LPS‐primed BMDC fail to secrete these cytokines in response to M. tuberculosis. We propose that LPS priming of BMDC, by exposure to high doses of LPS for 24 hr, stabilizes their tolerogenicity rather than promoting immunogenicity, and does so by multiple mechanisms, namely (i) generation of tolerogenic apoptotic BMDC through CD14:NFATc signalling; (ii) reduction of NF‐κB and IRF3 signalling and downstream pro‐inflammatory cytokine production; and (iii) blockade of inflammasome activation.

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“…In fact, we showed that IL-1b at 30-50 ng/ml alone is also capable of inducing a dose-dependent down-regulation of the expression of TLR4 in macrophages in vitro. This is a crucial molecule for LPS signalling which has recently been found to be down-regulated on peritoneal cells from LPS-tolerant mice [21]. Whether the mechanism triggered by IL-1b is similar to LPS is not known, although it had been previously demonstrated that TLR4-mediated signalling induced by LPS is homologous to that of IL-1 signalling [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…It has recently been shown that Toll-like receptor 4 (TLR4), an essential signalling receptor for LPS, is down-regulated in LPS-tolerant mouse peritoneal macrophages [21]. This downregulation correlates with the impairment of the production of pro-inflammatory cytokines such as TNF-a, IL-6 and IL-12.…”

Section: Il-1b Induces Down-regulation Of Tlr4 On Mouse Peritoneal Mamentioning

confidence: 99%

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

Alves-Rosa

Vulcano

Beigier-Bompadre

et al. 2002

Clinical and Experimental Immunology

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SUMMARYEndotoxin or lipopolysaccharide (LPS) tolerance may be partially due to the secretion of potent antiinflammatory cytokines following severe Gram-negative infections, or by low doses of LPS. In this work, we describe the effects of interleukin-1b (IL-1b) and tumour necrosis factor alpha (TNF-a), two early cytokines secreted after LPS exposure, in the induction of LPS tolerance. Our results demonstrate that mice treated with three daily doses of 100 ng of IL-1b were tolerant to LPS-induced shock. However, TNF-a was unable to induce an LPS refractory state. Given the fact that 100 ng of IL-1b increase the plasma levels of glucocorticoids, we evaluated whether a daily injection of dexamethasone (DEX) alone was able to reproduce the LPS-like tolerant state. However, no signs of LPS refractoriness were detected, except when DEX was administered concomitantly with a dose of IL-1b that does not induce corticosterone secretion (12 ng/mouse). This dose was found to induce in vitro up-regulation of the glucocorticoid receptors (GcR) of peritoneal macrophages following 24 h of treatment. In addition, we demonstrate that IL-1b is capable of inducing the down-regulation of Toll-like receptor 4 (TLR4), a crucial molecule in the signal transduction of LPS. Taken together, our results indicate that IL-1b can generate tolerance to LPS in vivo, and suggest that the regulation of mechanisms of the downregulation of TLR4, as well as those involved in the expression of GcR and/or in the secretion of glucocorticoids, would be crucial for these effects.

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Cutting Edge: Endotoxin Tolerance in Mouse Peritoneal Macrophages Correlates with Down-Regulation of Surface Toll-Like Receptor 4 Expression

Cited by 693 publications

References 30 publications

A unique role for p53 in the regulation of M2 macrophage polarization

A unique role for p53 in the regulation of M2 macrophage polarization

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

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