Introduction. Type I interferons (IFN-I) can be both anti- and pro-inflammatory. Their role is controversial in rheumatoid arthritis (RA) and experimental models. We have evaluated for the first time the therapeutic effect of IFN-α in collagen-induced arthritis (CIA) which mimics RA.
Methods. Disease was induced by 2 immunizations with collagen/CFA in conditional transgenic mice over-expressing mouse IFN-α1 and non-transgenic littermates. Arthritis was followed by clinical evaluation and histology (inflammation/bone destruction). Pain was followed by stance/Von Frey tests. Plasma cytokines/anti-collagen antibodies were measured by Luminex/ELISA. Leukocytes sub-populations/polarization were analyzed by flow cytometry. Bone marrow cells were cultured with M-CSF/RANKL to evaluate osteoclasts. CD4+CD25+ regulatory T cells (Treg) and CD4+CD25- effector T cells (Teff) were purified by magnetic sorting. ATPase activity was determined in vitro. Treg inhibition of Teff activation (co-cultures) was measured by flow cytometry/ELISA. The in vivo therapeutic capacity of purified Treg was estimated by adoptive transfer.
Results. IFN-α1 induction before the first or even between both immunizations resulted in CIA protection/lower pain parameters. Anti-collagen antibody/IL-6 production were lower in IFN-α1+ mice but IL-5 was increased. Protected mice show decreased polarization to Th17/lower IL-17 secretion and increased polarization to Th2 and IFN-γ-positive Th1/NK cells. Osteoclastogenesis/osteoclast activity were decreased in IFN-α1+ mice. CIA protection in IFN-α1-overexpressing mice was associated with impaired bone marrow B cells while increased CD86+ neutrophils, and particularly with expansion of Treg with higher CD39/CTLA-4 expression, higher ATPase activity and higher capacity to inhibit Teff. Most importantly, adoptive transfer of those highly suppressive Treg purified from CIA-IFN-α1+ mice impaired CIA development in recipients in comparison to adoptive transfer of Treg purified from CIA-IFN-α1- mice.
Conclusions. Early induction of IFN-α1 production, even in seropositive mice, protects against arthritis, highlighting a therapeutic window. This work better defines the role of IFN-α and shows its potent modulatory effect in inflammatory arthritis.