Journal of Molecular Medicine

, 89:833 | Cite as

Danger signals activating innate immunity in graft-versus-host disease

  • Robert Zeiser
  • Olaf Penack
  • Ernst Holler
  • Marco Idzko
Review

Abstract

Extensive cell death with consecutive release of danger signals can cause immune-mediated tissue destruction. The abundance of cell death is likely to determine the relevance of the danger signals as physiological mechanisms that counteract immune activation may be overruled. Such constellation is conceivable in chemo-/radiotherapy-induced tissue damage, reperfusion injury, trauma, and severe infection. Studies on graft-versus-host disease (GvHD) development have to consider the effects of chemo-/radiotherapy-related tissue damage leading to the release of exogenous and endogenous danger signals. Our previous work has demonstrated a role for adenosine-5′-triphosphate (ATP) as an endogenous danger signal in GvHD. Besides ATP, uric acid or soluble extracellular matrix components are functional danger signals that activate the NLRP3 inflammasome when released from dying cells or from extracellular matrix. In contrast to sterile inflammation, GvHD is more complex since bacterial components that leak through damaged intestinal barriers and the skin can activate pattern recognition receptors and directly contribute to GvHD pathogenesis. These exogenous danger signals transmit immune activation via toll-like receptors and NOD-like receptors of the innate immune system. This review covers both the impact of endogenous and exogenous danger signals activating innate immunity in GvHD.

Keywords

Graft-versus-host disease Danger signals Innate immunity Adenosine triphosphate Purinergic receptors Extracellular matrix Pathogen-associated molecular patterns Pattern recognition receptors Toll-like receptors NOD-like receptors 

Abbreviations

APCs

Antigen-presenting cells

ASC

Apoptosis-associated speck-like protein containing caspase activation and recruitment domain

ATP

Adenosine-5′-triphosphate

CARD

Caspase recruitment domain

CpG

Cytosine–phosphate–guanine

DC

Dendritic cells

ECM

Extracellular matrix

GvHD

Graft-versus-host disease

IDO

Indoleamine 2,3-dioxygenase

MDP

Muramyl dipeptide

MSC

Mesenchymal stromal cells

NALP3

NACHT, LRR, and PYD domains-containing protein 3

NAD

Nicotinamide adenine dinucleotide

NLRs

NOD-like receptors

NLRPs

NACHT-, LRR-, and PYD-containing proteins

NODs

Nucleotide-binding oligomerization domain

PAMPs

Pathogen-associated molecular patterns

pDC

Plasmacytoid DC

PRR

Pattern recognition receptors

ROS

Reactive oxygen species

TLR

Toll-like receptors

Treg

Regulatory T-cells

UA

Uric acid

Notes

Acknowledgments

We apologize to those whose work was not cited due to space limitations.

Grant support

This study was supported by the Deutsche Forschungsgemeinschaft, Germany (ID 7/4-2 to M.I., ZE 872/1-1 and Heisenberg Fellowship to R.Z. and PE 1450/1-1 to O.P.) and the Deutsche Krebshilfe, Germany (ID 108977 to O.P.).

Conflict of interests

The authors declare no competing financial interests.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Robert Zeiser
    • 1
  • Olaf Penack
    • 2
  • Ernst Holler
    • 3
  • Marco Idzko
    • 4
  1. 1.Department of Hematology and OncologyFreiburg University Medical Center, Albert-Ludwigs-UniversityFreiburgGermany
  2. 2.Department of Hematology and OncologyCharité, Campus Benjamin FranklinBerlinGermany
  3. 3.Department of Hematology and OncologyUniversity of RegensburgRegensburgGermany
  4. 4.Department of PneumologyFreiburg University Medical Center, Albert-Ludwigs-UniversityFreiburgGermany

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