Abstract
Chemokine synergy-inducing molecules are emerging as regulating factors in cell migration. The alarmin HMGB1, in its reduced form, can complex with CXCL12 enhancing its activity on monocytes via the chemokine receptor CXCR4, while the form containing a disulfide bond, by binding to TLR2 or TLR4, initiates a cascade of events leading to production of cytokines and chemokines. So far, the possibility that the CXCL12/HMGB1 heterocomplex could be maintained in chronic inflammation was debated, due to the release of reactive oxygen species. Therefore, we have assessed if the heterocomplex could remain active in Rheumatoid Arthritis (RA) and its relevance in the disease assessment. Monocytes from RA patients with active disease require a low concentration of HMGB1 to enhance CXCL12-induced migration, in comparison to monocytes from patients in clinical remission or healthy donors. The activity of the heterocomplex depends on disease activity, on the COX2 and JAK/STAT pathways, and is determined by the redox potential of the microenvironment. In RA, the presence of an active thioredoxin system correlates with the enhanced cell migration, and with the presence of the heterocomplex in the synovial fluid. The present study highlights how, in an unbalanced microenvironment, the activity of the thioredoxin system plays a crucial role in sustaining inflammation. Prostaglandin E2 stimulation of monocytes from healthy donors is sufficient to recapitulate the response observed in patients with active RA. The activation of mechanisms counteracting the oxidative stress in the extracellular compartment preserves HMGB1 in its reduced form, and contributes to fuel the influx of inflammatory cells. Targeting the heterocomplex formation and its activity could thus be an additional tool for dampening the inflammation sustained by cell recruitment, for those patients with chronic inflammatory conditions who poorly respond to current therapies.
Highlights
The concomitant presence of pro-inflammatory cytokines [1, 2], growth factors [3], prostaglandins [4], as well as chemokines [5] orchestrate the characteristic features of Rheumatoid Arthritis (RA)
Since we previously described that the heterocomplex enhanced monocyte migration on human monocytes from healthy donors (HD) via CXCR4 [21], we evaluated its activity on monocytes from patients with RA, which are exposed to pro-inflammatory stimuli in the circulation
Monocytes from patients with active RA, or in clinical remission, did not differ in their capability to respond to CXCL12 (Figure 1A), and as demonstrated in monocytes from HD [21], they did not migrate in response to HMGB1 alone
Summary
The concomitant presence of pro-inflammatory cytokines [1, 2], growth factors [3], prostaglandins [4], as well as chemokines [5] orchestrate the characteristic features of Rheumatoid Arthritis (RA). An impressive amount of preclinical and clinical evidence has progressively validated the role of chemokines and their receptors in immune-mediated diseases [12], which led to the development of several chemokine receptor blocking agents, initially tested with success in RA pre-clinical models [13]. Most of these competitive chemokine receptor antagonists have disappointed when their efficacy was assessed in clinical trials [5, 14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
