Elsevier

Molecular Immunology

Volume 55, Issue 1, August 2013, Pages 76-82
Molecular Immunology

Review
HMGB1 and leukocyte migration during trauma and sterile inflammation

https://doi.org/10.1016/j.molimm.2012.10.037Get rights and content

Abstract

HMGB1 is a nuclear protein that is released or secreted following trauma or severe cellular stress. Extracellular HMGB1 triggers inflammation and recruits leukocytes to the site of tissue damage. We review recent evidence that the ability of HMGB1 to recruit leukocytes may be entirely due to the formation of a heterocomplex with the homeostatic chemokine CXCL12. The HMGB1–CXCL12 heterocomplex acts on the CXCR4 receptor more potently than CXCL12 alone. Notably, only one of the redox forms of HMGB1, the one where all cysteines are reduced (all-thiol), can bind CXCL12. Both HMGB1 containing a disulfide bond between C23 and C45, which induces chemokine and cytokine release by activating TLR4, and HMGB1 terminally oxidized to contain a cysteine sulfonate are inactive in recruiting leukocytes. Thus, the chemoattractant and cytokine-inducing activities of HMGB1 are separable, and we propose that they appear sequentially during the development of inflammation and its resolution. The HMGB1–CXCL12 heterocomplex constitutes a specific target that may hold promise for the treatment of several pathologies.

Highlights

► A specific complex between HMGB1 and CXCL12 directs leukocyte migration via CXCR4. ► HMGB1 attracts leukocytes to injury sites and activates them, but via different receptors. ► Only the fully reduced (all-thiol) form of HMGB1 forms the heterocomplex with CXCL12. ► The HMGB1–CXCL12 heterocomplex is a specific therapeutic target.

Introduction

Humans are confronted with two types of assaults on their integrity: infection and trauma. Both cause damage to our tissues, but while infection is a struggle with pathogens, trauma that does not breach our skin or mucosa does not allow the entry of pathogens and is called “sterile”. The response to sterile trauma can help us understand how tissues recover and heal after damage.

Healing after sterile tissue damage is an evolutionarily conserved, complex, multicellular process that is organized in three phases: inflammation, cell proliferation and remodeling. They involve the coordinated efforts of several cell types, including the parenchymal cells of the tissue, fibroblasts, endothelial and immune cells. The coordination requires a complex signaling network involving damage associated molecular patterns (DAMPs) and their receptors, growth factors, cytokines and chemokines. DAMPs are molecules leaked by dead cells or secreted by severely stressed cells, that alert the immune system to the occurrence of tissue damage. Cytokines are intercellular mediators mainly involved in the regulation of immunity, hematopoiesis and inflammation. Chemokines, a subclass of cytokines, have a crucial role as chemoattractants to guide the migration of cells.

The present review will focus on a single protein, High Mobility Group Box 1 (HMGB1), that can play roles as DAMP, chemokine, cytokine and growth factor, and orchestrate the action of other actors, during the entire process from tissue damage to healing.

Section snippets

HMGB1

HMGB1 is a highly conserved non-histone nuclear protein organized into two DNA-binding domains, HMG box A and B, and a negative charged C-terminal tail (Fig. 1). Nuclear HMGB1 binds to the minor groove of DNA, and participates in stabilizing nucleosomes and regulation of gene expression (Celona et al., 2011).

In addition to its nuclear role, HMGB1 functions as a signal of tissue damage, and therefore is considered the archetype DAMP or “alarmin” (Bianchi, 2007). When cells die after trauma or

The HMGB1-RAGE axis

Cell migration requires mechanical actions that occur via cytoskeleton rearrangements. The first evidence for HMGB1-induced reorganization of the cytoskeleton was obtained when HMGB1-coated surfaces were found to strongly promote neurite extension in embryonic forebrain neurons (Rauvala and Pihlaskari, 1987). Extracellular HMGB1 was later found to promote the migration of smooth muscle cells (Degryse et al., 2001) and many other cell types (Rauvala and Rouhiainen, 2010).

HMGB1-dependent cell

A new player in leukocyte recruitment: the CXCL12-HMGB1–CXCR4 axis

More than ten years ago, it was shown that the migration of cells toward HMGB1 can be blocked by pertussis toxin (PTX), suggesting the involvement of a G protein-coupled receptor (GPCR) associated to Gi/o proteins (Degryse et al., 2001); later on, this observation was independently confirmed (Yang et al., 2007). We also surprisingly found that HMGB1-induced cell migration requires protein synthesis, a requirement shared by cell migration induced by CXCL12 (previously called SDF-1) but no other

HMGB1 and redox: a new focus

HMGB1 has three conserved cysteines in positions 23 and 45 within Box A, and position 106 in Box B (Fig. 1). Cysteines 23 and 45 are ideally placed to form an intramolecular disulfide bond while C106 remains unpaired, and is important for the interaction of HMGB1 with TLR4 receptor (Yang et al., 2010). The cytosol and the nucleus have a strongly negative (reducing) redox potential, and intracellular HMGB1 is largely in the reduced state (Hoppe et al., 2006, Venereau et al., 2012). However, the

HMGB1 plays multiple roles during sterile inflammation

We propose that HMGB1 orchestrates both key events in sterile inflammation, leukocyte recruitment and their induction to secrete inflammatory cytokines, by both engaging CXCL12 and acting solo. We observed in a model of muscle injury induced by cardiotoxin (CTX) that different redox forms of HMGB1 are released sequentially: all-thiol-HMGB1 is released first and disulfide-bonded later (Fig. 3) (Venereau et al., 2012). Within a tissue, any cell occupies a limited space, which will be left vacant

The HMGB1–CXCL12 heterocomplex as a therapeutic target

Targeting HMGB1 appears as a promising approach for drug development, since numerous studies have implicated HMGB1 and its receptors in a large number of diseases including atherosclerosis, rheumatoid arthritis, sepsis and cancer. Indeed, aiming at the HMGB1–CXCL12 complex, rather than to HMGB1, might have distinct advantages. Notably, other activities of HMGB1 appear completely independent from the formation of the heterocomplex with CXCL12; indeed, HMGB1-induced TNF secretion proceeds via

Conclusion

The data discussed in this review have elucidated that the chemoattractant activity of HMGB1 can be separated from the cytokine-inducing activity, as the former depends on the interaction with CXCL12 and the CXCR4 receptor, and on a specific redox state of HMGB1 (all-thiol). RAGE and NF-κB activation are apparently required to sustain the production of CXCL12, which is used autocrinally. HMGB1, CXCL12 and CXCR4 are all highly conserved in the vertebrate lineage (Sessa and Bianchi, 2007, Zlotnik

Acknowledgments

Our labs are funded by grants from European Union (INNOCHEM, LSHB-CT-2005-518167, ADITEC 280873 and TIMER,281608), the Swiss National Science Foundation, the San Salvatore Foundation, the Helmut Horten Foundation, the Institute for Arthritis Research, the Novartis Foundation to M.U., and Ministero della Salute, Fondazione Cariplo and Associazione Italiana Ricerca sul Cancro (AIRC) to M.E.B.

E.V. is supported by a fellowship from AIRC.

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    This article belongs to Special Issue on Leukocyte Adhesion and Migration.

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    Both authors equally contributed to the work.

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