Open Access

Targeting RAGE in sepsis

Critical Care200812:103

https://doi.org/10.1186/cc6187

Published: 11 January 2008

Abstract

The receptor of advanced glycation endproducts (RAGE) is a multiligand receptor that upon activation causes sustained activation of multiple inflammatory pathways. Recent evidence, summarized in a review by Bopp and colleagues in this issue of Critical Care, has implicated RAGE as a potential therapeutic target in sepsis. Here, we discuss several open issues that need to be addressed before anti-RAGE strategies can enter the sepsis clinical trial arena.

In a review in this issue of Critical Care, Bopp and colleagues [1] summarize current knowledge on the receptor of advanced glycation endproducts (RAGE) and its potential as a new therapeutic target in sepsis. RAGE is expressed in many cell types involved in the innate immune system and is able to recognize a wide range of endogenous molecules that are released during various conditions of inflammation and/or injury. Collectively, these endogenous molecules, which warn the host of imminent danger, have been called alarmins or danger-associated molecular patterns [2]. An important example of an alarmin and an established ligand for RAGE with relevance for sepsis is high-mobility group box 1 (HMGB1) [3].

Activation of RAGE results in sustained activation of nuclear factor-kappa B (NF-κB), thereby converting transient pro-inflammatory responses into lasting cellular dysfunction [4]. The evidence that inhibition of RAGE may be beneficial in sepsis is derived from what is, thus far, a limited number of studies. In a hallmark study published in 2004, Liliensiek and colleagues [5] reported that RAGE-deficient mice were strongly protected against lethality due to polymicrobial sepsis caused by cecal ligation and puncture (CLP). The protection provided by the lack of RAGE was associated with a strongly reduced activation of NF-κB in the peritoneum and lungs, which in wild-type mice was abundantly present, suggesting that the absence of excessive NF-κB activation in RAGE-deficient mice might have contributed to their reduced mortality [5]. In addition, RAGE deficiency resulted in a diminished accumulation of inflammatory cells in the peritoneum, which is in line with an earlier investigation by the same group of authors identifying RAGE as a counter-receptor for the β2-integrin Mac-1 (CD11b/CD18) and thereby as a mediator of leukocyte recruitment and adhesion [6]. Moreover, other authors have demonstrated that RAGE-deficient mice are partially protected against lethality due to endotoxin shock [7]. It is likely that the protective effect of RAGE inhibition in experimental sepsis is due, at least in part, to inhibition of one of its ligands, HMGB1. Indeed, HMGB1 is released in the circulation during experimental and clinical sepsis and an anti-HMGB1 antibody protected against endotoxin- and CLP-induced lethality [8, 9]. Importantly, HMGB1 can activate not only RAGE but also other receptors, most notably Toll-like receptors 2 and 4 [3], and anti-HMGB1 treatment caused an additional survival benefit in RAGE-deficient mice injected with high-dose endotoxin, suggesting that HMGB1 acts only partially via RAGE during endotoxin shock [7].

Which questions remain to be answered to further establish a role for RAGE in sepsis and to obtain further support for the notion that RAGE may be a therapeutic target in this syndrome? When addressing this question, one needs to consider that the historic concept of the pathogenesis of sepsis implicating mortality as the consequence of an uncontrolled hyperinflammatory response of the host has been modified. The scientific community now agrees that this paradigm is oversimplified and only partially true [10]. The extent and duration of hyperinflammation likely vary due to differences in the comorbidity, nutritional status, age, and genetic background of the patient, on the one hand, and the initial source of the infection, the virulence of the causing organism, and the size of the infectious inoculum on the other hand. In most if not all patients who survive the acute phase of sepsis, a prolonged state of immune suppression evolves; this condition is referred to as immunoparalysis [11]. Moreover, experimental studies have indicated that a certain degree of inflammation is necessary to mount an effective innate immune response to invading pathogens. As such, RAGE inhibition may be ineffective or even harmful in some infectious conditions. Therefore, more research is required to situate RAGE in a position that warrants clinical trials in patients with sepsis. In this respect, one could think of studies on RAGE inhibition in pneumonia, considering that the lung not only is the most frequent cause of sepsis in humans [12] but also represents an organ in which RAGE is abundantly expressed [13]. In addition, experiments in which anti-RAGE treatment is delayed until after bacterial infection (peritonitis and pneumonia) and combined with antibiotic therapy should be considered. Moreover, more studies need to be conducted on the role of RAGE in critical organ derangements implicated in the pathogenesis of sepsis, including activation of the coagulation system and the complement system. Until then, RAGE remains a potential yet promising therapeutic target in sepsis which awaits further research.

Abbreviations

CLP : 

= cecal ligation and puncture

HMGB1 : 

= high-mobility group box 1

NF-κB : 

= nuclear factor-kappa B

RAGE : 

= receptor of advanced glycation endproducts.

Declarations

Authors’ Affiliations

(1)
Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical CenterUniversity of Amsterdam
(2)
Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center,University of Amsterdam

References

  1. Bopp C, Bierhaus A, Hofer S, Bouchon A, Nawroth PP, Martin E, Weigand ME: Bench-to-bedside review: The inflammation-perpetuating pattern-recognition receptor RAGE as a therapeutic target in sepsis. Crit Care 2008, 12: 201. 10.1186/cc6164PubMed CentralView ArticlePubMedGoogle Scholar
  2. Bianchi ME: DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 2007, 81: 1-5. 10.1189/jlb.0306164View ArticlePubMedGoogle Scholar
  3. Lotze MT, Tracey KJ: High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005, 5: 331-342. 10.1038/nri1594View ArticlePubMedGoogle Scholar
  4. Bierhaus A, Stern DM, Nawroth PP: RAGE in inflammation: a new therapeutic target? Curr Opin Investig Drugs 2006, 7: 985-991.PubMedGoogle Scholar
  5. Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plachky J, Grone HJ, Kurschus FC, Schmidt AM, et al.: Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest 2004, 113: 1641-1650. 10.1172/JCI200418704PubMed CentralView ArticlePubMedGoogle Scholar
  6. Chavakis T, Bierhaus A, Al Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT, et al.: The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med 2003, 198: 1507-1515. 10.1084/jem.20030800PubMed CentralView ArticlePubMedGoogle Scholar
  7. Abeyama K, Stern DM, Ito Y, Kawahara K, Yoshimoto Y, Tanaka M, Uchimura T, Ida N, Yamazaki Y, Yamada S, et al.: The N-terminal domain of thrombomodulin sequesters high-mobility group-B1 protein, a novel antiinflammatory mechanism. J Clin Invest 2005, 115: 1267-1274. 10.1172/JCI200522782PubMed CentralView ArticlePubMedGoogle Scholar
  8. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, et al.: HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999, 285: 248-251. 10.1126/science.285.5425.248View ArticlePubMedGoogle Scholar
  9. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, et al.: Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 2004, 101: 296-301. 10.1073/pnas.2434651100PubMed CentralView ArticlePubMedGoogle Scholar
  10. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003, 348: 138-150. 10.1056/NEJMra021333View ArticlePubMedGoogle Scholar
  11. Volk HD, Reinke P, Docke WD: Clinical aspects: from systemic inflammation to 'immunoparalysis'. Chem Immunol 2000, 74: 162-177.View ArticlePubMedGoogle Scholar
  12. Annane D, Bellissant E, Cavaillon JM: Septic shock. Lancet 2005, 365: 63-78. 10.1016/S0140-6736(04)17667-8View ArticlePubMedGoogle Scholar
  13. Morbini P, Villa C, Campo I, Zorzetto M, Inghilleri S, Luisetti M: The receptor for advanced glycation end products and its ligands: a new inflammatory pathway in lung disease? Mod Pathol 2006, 19: 1437-1445.PubMedGoogle Scholar

Copyright

© BioMed Central Ltd 2008

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