HMGB1 promotes recruitment of inflammatory cells to damaged tissues by forming a complex with CXCL12 and signaling via CXCR4

After tissue damage, inflammatory cells infiltrate the tissue and release proinflammatory cytokines. HMGB1 (high mobility group box 1), a nuclear protein released by necrotic and severely stressed cells, promotes cytokine release via its interaction with the TLR4 (Toll-like receptor 4) receptor and cell migration via an unknown mechanism. We show that HMGB1- induced recruitment of inflammatory cells depends on CXCL12. HMGB1 and CXCL12 form a heterocomplex, which we characterized by nuclear magnetic resonance and surface plasmon resonance, that acts exclusively through CXCR4 and not through other HMGB1 receptors. Fluorescence resonance energy transfer data show that the HMGB1–CXCL12 heterocomplex promotes different conformational rearrangements of CXCR4 from that of CXCL12 alone. Mononuclear cell recruitment in vivo into air pouches and injured muscles depends on the heterocomplex and is inhibited by AMD3100 and glycyrrhizin. Thus, inflammatory cell recruitment and activation both depend on HMGB1 via different mechanisms

Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release

Tissue damage causes inflammation, by recruiting leukocytes and activating them to release proinflammatory mediators. We show that high-mobility group box 1 protein (HMGB1) orchestrates both processes by switching among mutually exclusive redox states. Reduced cysteines make HMGB1 a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine and further cysteine oxidation to sulfonates by reactive oxygen species abrogates both activities. We show that leukocyte recruitment and activation can be separated. A nonoxidizable HMGB1 mutant in which serines replace all cysteines (3S- HMGB1) does not promote cytokine production, but is more effective than wild-type HMGB1 in recruiting leukocytes in vivo. BoxA, a HMGB1 inhibitor, interferes with leukocyte recruitment but not with activation. We detected the different redox forms of HMGB1 ex vivo within injured muscle. HMGB1 is completely reduced at first and disulfide-bonded later. Thus, HMGB1 orchestrates both key events in sterile inflammation, leukocyte recruitment and their induction to secrete inflammatory cytokines, by adopting mutually exclusive redox states

Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release

Tissue damage causes inflammation, by recruiting leukocytes and activating them to release proinflammatory mediators. We show that high-mobility group box 1 protein (HMGB1) orchestrates both processes by switching among mutually exclusive redox states. Reduced cysteines make HMGB1 a chemoattractant, whereas a disulfide bond makes it a proinflammatory cytokine and further cysteine oxidation to sulfonates by reactive oxygen species abrogates both activities. We show that leukocyte recruitment and activation can be separated. A nonoxidizable HMGB1 mutant in which serines replace all cysteines (3S- HMGB1) does not promote cytokine production, but is more effective than wild-type HMGB1 in recruiting leukocytes in vivo. BoxA, a HMGB1 inhibitor, interferes with leukocyte recruitment but not with activation. We detected the different redox forms of HMGB1 ex vivo within injured muscle. HMGB1 is completely reduced at first and disulfide-bonded later. Thus, HMGB1 orchestrates both key events in sterile inflammation, leukocyte recruitment and their induction to secrete inflammatory cytokines, by adopting mutually exclusive redox states

Possible mechanisms involved in chemokine synergy fine tuning the inflammatory response

The arrest and directed migration of leukocytes during homeostasis, tumour development and inflammation is orchestrated by a multitude of chemokines, which govern leukocyte migratory activities. Immune cells are particularly adept at adjusting rapidly to changes within the environment by migration in response to chemokines. The confrontation of leukocytes with different combination of chemokines that are concomitantly produced under physiological or pathological conditions in vivo is complex. There are different ways to enhance or reduce leukocyte migration mediated by chemokines such as posttranslational modifications. Here, we described a positive regulatory mechanism in leukocyte trafficking, by the synergism between chemokines to rapidly augment the local leukocyte influx, thereby enhancing the outcome of an inflammatory response in vivo. The cellular mechanisms involved in chemokine synergy are still debated, but probably include chemokine and/or receptor heterodimerization and subsequent cooperation in signal transduction.status: publishe

Synergy-inducing chemokines enhance CCR2 ligand activities on monocytes

The migration of monocytes to sites of inflammation is largely determined by their response to chemokines. Although the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how cells integrate the messages provided by different chemokines that are concomitantly produced in physiological or pathological situations in vivo. We present evidence for one regulatory mechanism of human monocyte trafficking. Monocytes can integrate stimuli provided by inflammatory chemokines in the presence of homeostatic chemokines. In particular, migration and cell responses could occur at much lower concentrations of the CCR2 agonists, in the presence of chemokines (CCL19 and CCL21) that per se do not act on monocytes. Binding studies on CCR2(+) cells showed that CCL19 and CCL21 do not compete with the CCR2 agonist CCL2. Furthermore, the presence of CCL19 or CCL21 could influence the degradation of CCL2 and CCL7 on cells expressing the decoy receptor D6. These findings disclose a new scenario to further comprehend the complexity of chemokine-based monocyte trafficking in a vast variety of human inflammatory disorders

The interactive effect of some environmental factors on the growth, agar yield and quality of Gracilariopsis bailinae (Zhang et Xia) cultured in tanks

The single and interactive effects of light and temperature, salinity, and urea enrichment on the growth and agar yield and quality of Gracilariopsis bailinae were determined under indoor and outdoor tank conditions. Culture period was 6 weeks. Growth rate reached its peak on the second week in all culture conditions and gradually decreased towards the end of the culture period. Higher growth rates were obtained in seaweed cultured in outdoor (0.27-1.12% day-1) than in indoor (0.21-0.72% day-1) tanks; with urea enrichment and lower salinity levels (15-25ppt). A significant interactive effect was demonstrated between and among the environmental parameters on the growth of the seaweed. Highest gel strength (870 g cm-1) and lowest sulfate content (3.1 µg mg-1) were obtained at 25ppt, without urea enrichment and in indoor tanks. A significant interactive effect of light intensity and temperature-urea enrichment was ascertained on agar yield; also of light intensity and temperature-salinity on gel strength and sulfate content. Positive and negative correlation was likewise established between agar properties