CXCL12 forms a complex with HMGB1 that binds to the chemokine receptor CXCR4 and increases inflammatory cell migration.

HMGB1 orchestrates leukocyte recruitment and their induction to secrete inflammatory cytokines by switching between mutually exclusive redox states.

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Primary central nervous system lymphomas (PCNSL) are aggressive malignancies confined to the CNS, mostly of diffuse large B-cell histotype. Despite improved understanding of the malignant B cells, little is known on the tumor microenvironment and on the response of the adaptive immunity against PCNSL. We investigated the phenotype of tumor infiltrating lymphocytes (TILs), and the expression of chemokines that could affect malignant B cells and trafficking of TILs. TILs and chemokine expression were evaluated by immunohistochemistry and in situ hybridization. Furthermore, we performed in vitro migration assays to analyze the migratory capacity of lymphocytes and malignant B cells toward chemokines and chemokine heterocomplexes. We show in 22 cases of PCNSL from immunocompetent patients that CD81 T cells represent the majority of TILs in the tumor mass. They tend to accumulate in perivascular areas, show Granzyme B expression and proliferate in situ. Their localization and density correlates with the expression of the inflammatory chemokine CXCL9, which is transcribed and translated by perivascular macrophages and pericytes in the perivascular microenvironment. Moreover, CXCL9 and CXCL12 are coexpressed on the tumor vasculature and form heterocomplexes. In the presence of CXCL9, CXCL12-induced migration is enhanced not only on CXCR4 1 /CXCR3 1 /CD8 1 T cells but also on CXCR4 Primary central nervous system lymphomas (PCNSL) are aggressive malignancies confined to the central nervous system (CNS), mostly of diffuse large B-cell histotype. It counts for about 5% of primary CNS tumors and its incidence augmented significantly over the last 3 decades. 1,2 Despite improved therapeutic intervention, the prognosis of PCNSL remains poor. The majority of previous studies on PCNSL focused on the phenotype of malignant B cells and only recent findings indicate a potential role of the microenvironment.3 Moreover, recent studies in various tumors highlight the importance of the environment for neoplastic development and progression. 4 Type, density and location of different tumor infiltrating lymphocytes (TILs) influence clinical outcome due to the recruitment of T-cell subsets that provide tumor-suppressive or tumor-promoting stimuli.5 To improve our knowledge on the tumor pathophysiology, it is therefore essential to investigate the T-cell subsets that are attracted to the tumor and the chemotactic stimuli, which regulate their recruitment. [6][7][8] Unlike most other organs, the CNS is an immunoprivileged site with restricted access and unique microenvironment that profoundly affects the capacity of T cells to enter and exert their functions.9 Lymphocyte recruitment is regulated by the chemokine receptors expressed on their surface and by selective chemokines expressed in tissues. In addition,

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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.

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