Requirement of HMGB1 for stromal cell–derived factor–1/CXCL12–dependent migration of macrophages and dendritic cells

Abstract

HMGB1 finely tunes the function of DCs, thus influencing their maturation program and eventually the establishment of adaptive, T cell-dependent immune responses. Moreover, it promotes the up-regulation of receptors for lymph node chemokines, regulates the remodeling of the cytoskeleton of migrating cells, and sustains their journey to secondary lymphoid organs via a RAGE-dependent pathway. The inflammatory properties of HMGB1 depend at least partially on the ability to complex with soluble moieties, including nucleic acids, microbial products, and cytokines. Here, we show that bone marrow-derived mouse DCs release HMGB1 during CXCL12-dependent migration in vitro. Macrophages share this property, suggesting that it may be a general feature of CXCL12-responsive leukocytes. The chemotactic response to rCXCL12 of DCs and macrophages abates in the presence of the HMGB1 antagonist BoxA. HMGB1 secreted from DCs and macrophages binds to CXCL12 in the fluid phase and protects the chemokine conformation and function in a reducing environment. Altogether, our data indicate that HMGB1 release is required for CXCL12 ability to attract myeloid-derived cells and reveal a functional interaction between the two molecules that possibly contributes to the regulation of leukocyte recruitment and motility.

Necrotic cell-derived high mobility group box 1 attracts antigen-presenting cells but inhibits hepatocyte growth factor-mediated tropism of mesenchymal stem cells for apoptotic cell death

“…28,29 In addition, RAGE dependency of its migratory effect suggests that HMGB1 by itself acts as a chemoattractant and does not require the formation of complexes with CXCL12, because these have been reported to signal via C-X-C chemokine receptor type 4 (CXCR4). 32,41 This conclusion is further supported by the under-agarose migration assay employed here: when recombinant HMGB1 was used as a target, only a stable gradient of HMGB1 could form, along which the cells could migrate, whereas the concentration of CXCL12, if produced by the monocytes and iDC, would have been highest at the site of these cells. HMGB1/RAGE-mediated attraction of monocytes/ macrophages and iDC has also been described by others.…”

PDGFRα-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia

“…HMGB1 can act as a mobile and dynamic nucleo-cytoplasmic protein influencing multiple processes in chromatin such as transcription, replication, recombination, and DNA repair (39,40), but HMGB1 can also be secreted into the extracellular milieu as a signaling molecule when cells are stressed (41). HMGB1 can bind exogenous and endogenous agents such as endotoxin, microbial DNA, and nucleosomes, and induces adaptive and innate immune responses via TLR2/4/9 followed by NF-κB activation (42,43), contributing to inflammation, autoimmune dysregulation, and carcinogenesis. However, purified recombinant HMGB1 has little, if any, proinflammatory activity (44).…”

Cell death, clearance and immunity in the skeletal muscle

“…Indeed, oxidation abrogates both muscle stem cell migration in response to HMGB1 and their ability to differentiate into myofibers in vitro. 25,32,38,39 The early antioxidant response in regenerating muscle might limit HMGB1 oxidation, thus allowing the timely recruitment of leukocytes, the activation of muscle stem cells, the reconstitution of the vasculature and the eventual successful muscle regeneration. 25,39 Of importance, HMGB1 expression is modulated upon persistent immune-mediated damage of the muscle during inflammatory myopathies, suggesting that its generation might contribute to the natural history of these conditions.…”