Development of endotoxin tolerance in humans in vivo

Draisma, Annelies; Pickkers, Peter; Bouw, Martijn P.W.J.M.; Hoeven, Johannes G. van der

doi:10.1097/ccm.0b013e31819c3c67

Cited by 131 publications

(117 citation statements)

References 50 publications

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“…Therefore, it could be possible that the absence of PMNs results in an inability to dampen proinflammatory cytokine production like IL-1, which results in fever. In human experimental endotoxemia, exposure to bacterial endotoxin (LPS) leads to hyporesponsiveness to a new endotoxin challenge (55). It has been described that reduced TNF-a production plays a major role in endotoxin tolerance.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-Mediated Inhibition of Proinflammatory Cytokine Responses

Gresnigt

Joosten

Verschueren

et al. 2012

The Journal of Immunology

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Neutrophils (polymorphonuclear neutrophils [PMNs]) play an elaborate role in the innate immune response against invading pathogens. Recent research provided evidence that PMNs can play a modulatory role in inflammation next to their primary role of phagocytosis. In the current study, we investigated whether neutrophils can modulate the innate immune response against Candida albicans. Production of the proinflammatory cytokines IL-1β and TNF-α by human PBMCs in response to C. albicans or LPS was decreased by coculture of PMNs; however, the anti-inflammatory cytokine IL-10 remained unaffected. Using Transwells and cells of patients with chronic granulomatous disease, we show that this downregulation of proinflammatory cytokine production was independent of phagocytosis and reactive oxygen species but was dependent on a soluble factor. We suggest that neutrophil-derived proteases are responsible for the downregulation of IL-1β and TNF-α, as cytokine production could be recovered by addition of α1-antitrypsin, an endogenous inhibitor of serine proteases. PMN lysates and neutrophil elastase could degrade recombinant human IL-1β and TNF-α but not IL-10, and this could be inhibited by addition of α1-antitrypsin. Moreover, we also provide evidence that the dampening effect of PMNs is present in vivo in a murine zymosan-induced arthritis model and a murine experimental endotoxemia model. Altogether, our data show that PMNs can dampen the proinflammatory response to C. albicans by protease-mediated degradation of cytokines. This observation suggest that PMNs might play a important regulatory role in the host defense against C. albicans and can be important for understanding the regulation of inflammation in general.

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Section: Discussionmentioning

confidence: 99%

Neutrophil-Mediated Inhibition of Proinflammatory Cytokine Responses

Gresnigt

Joosten

Verschueren

et al. 2012

The Journal of Immunology

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“…It was reported that the expression of TGF-␤1 significantly increased in endotoxin-tolerized human peritoneal macrophages (33), mouse macrophages (34), mouse dendritic cells (35), and human blood from sepsis patients (36). TGF-␤1 is also a major immunosuppressive cytokine and plays a vital role in the development of endotoxin tolerance (34,37).…”

Section: Siglec-1 Expression Significantly Up-regulated During Lpsindmentioning

confidence: 99%

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

Lan

Ren

et al. 2016

Journal of Biological Chemistry

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Sepsis is one of the leading causes of death worldwide. Although the prevailing theory for the sepsis syndrome is a condition of uncontrolled inflammation in response to infection, sepsis is increasingly being recognized as an immunosuppressive state known as endotoxin tolerance. We found sialylation of cell surface was significantly increased on LPS-induced tolerant cells; knockdown of Neu1 in macrophage cell line RAW 264.7 cells resulted in enhanced LPS-induced tolerance, whereas overexpression of Neu1 or treatment with sialidase abrogated LPS-induced tolerance, as defined by measuring TNF-␣ levels in the culture supernatants. We also found that the expression of Siglec-1 (a member of sialic acid-binding Ig (I)-like lectin family members, the predominant sialic acid-binding proteins on cell surface) was specifically up-regulated in endotoxin tolerant cells and the induction of Siglec-1 suppresses the innate immune response by promoting TGF-␤1 production. The enhanced TGF-␤1 production by Siglec-1 was significantly attenuated by spleen tyrosine kinase (Syk) inhibitor. Knockdown of siglec-1 in RAW 264.7 cells resulted in inhibiting the production of TGF-␤1 by ubiquitin-dependent degradation of Syk. Mechanistically, Siglec-1 associates with adaptor protein DNAX-activation protein of 12 kDa (DAP12) and transduces a signal to Syk to control the production of TGF-␤1 in endotoxin tolerance. Thus, Siglec-1 plays an important role in the development of endotoxin tolerance and targeted manipulation of this process could lead to a new therapeutic opportunity for patients with sepsis.Sepsis is generally defined as a systemic inflammatory response syndrome in response to infection. Sepsis can be potentially life threatening; of more than 1 million Americans who are diagnosed with severe sepsis every year, between 28 and 50% will die from this disease (1, 2). It is well-recognized that patients with sepsis are often immune suppressed, a state of reduced responsiveness to endotoxin known as endotoxin tolerance, deaths in this immunosuppressive phase are typically due to failure to control the secondary infections (3-5). The molecular mechanisms underlying this endotoxin tolerance phenomenon is poorly understood.Sialic acids are a family of nine-carbon acidic monosaccharides and are involved in immune response, such as host-pathogen recognition, migration, and antigen presentation. Mounting experimental evidence suggests that the presence of sialic acid residue act as a marker of self in the immune system, as such residues are absent from most microbes (6). Indeed, host cells can be lysed by immune cytotoxic effector mechanisms after extensive desialylation, an observation that demonstrates the significant role played by cell surface sialic acids in the selfrecognition process (7). In addition, normal human serum contains natural antibodies to sialidase-treated red blood cells (7-9), lymphocytes (10), and thymocytes (7). Recently, Meesmann et al. showed that desialylation acted as an "eat me" signal and caused an enhanced upt...

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“…Leukocytes of septic patients are poorly responsive to pathogen-associated molecular patterns (PAMPs) compared with cells from healthy subjects, reminiscent of the phenomenon of endotoxin tolerance (18)(19)(20). This modified immune status may facilitate the occurrence of secondary infections (20,21).…”

mentioning

confidence: 99%

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

Souza-Fonseca-Guimarães

Parlato

Fitting

et al. 2012

The Journal of Immunology

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As sensors of infection, innate immune cells are able to recognize pathogen-associated molecular patterns by receptors such as TLRs. NK cells present in many tissues contribute to inflammatory processes, particularly through the production of IFN-γ. They may display a protective role during infection but also a detrimental role during sterile or infectious systemic inflammatory response syndrome. Nevertheless, the exact status of NK cells during bacterial sepsis and their capacity directly to respond to TLR agonists remain unclear. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors. The aim of this study was to gain insight into TLR2/TLR4/TLR9 expression on/in murine NK cells at the protein level and determine if their agonists were able to induce cytokine production. We show, by flow cytometry, a strong intracellular expression of TLR2 and a low of TLR4 in freshly isolated murine spleen NK cells, similar to that of TLR9. In vitro, purified NK cells respond to TLR2, TLR4, and TLR9 agonists, in synergy with activating cytokines (IL-2, IL-15, and/or IL-18), and produce proinflammatory cytokines (IFN-γ and GM-CSF). Finally, we explored the possible tolerance of NK cells to TLR agonists after a polymicrobial sepsis (experimental peritonitis). For the first time, to our knowledge, NK cells are shown to become tolerant in terms of proinflammatory cytokines production after sepsis. We show that this tolerance is associated with a reduction of the CD27+CD11b− subset in the spleen related to the presence of regulatory T cells and mainly mediated by TGF-β.

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Development of endotoxin tolerance in humans in vivo

Cited by 131 publications

References 50 publications

Neutrophil-Mediated Inhibition of Proinflammatory Cytokine Responses

Neutrophil-Mediated Inhibition of Proinflammatory Cytokine Responses

Induction of Siglec-1 by Endotoxin Tolerance Suppresses the Innate Immune Response by Promoting TGF-β1 Production

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

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