Despite intensive research on rheumatoid arthritis, the pathomechanism of the disease
is still not fully understood and the treatment has not been completely resolved.
Previously we demonstrated that the GTPase-activating protein, ARHGAP25 has a crucial
role in the regulation of basic phagocyte functions. Here we investigate the role
of ARHGAP25 in the complex inflammatory process of autoantibody-induced arthritis.Wild-type
and ARHGAP25 deficient (KO) mice on a C57BL/6 background, as well as bone marrow chimeric
mice, were treated i.p. with the K/BxN arthritogenic or control serum, and the severity
of inflammation and pain-related behavior was measured. Histology was prepared, leukocyte
infiltration, cytokine production, myeloperoxidase activity, and superoxide production
were determined, and comprehensive western blot analysis was conducted.In the absence
of ARHGAP25, the severity of inflammation, joint destruction, and mechanical hyperalgesia
significantly decreased, similarly to phagocyte infiltration, IL-1β, and MIP-2 levels
in the tibiotarsal joint, whereas superoxide production or myeloperoxidase activity
was unchanged. We observed a significantly mitigated phenotype in KO bone marrow chimeras
as well. In addition, fibroblast-like synoviocytes showed comparable expression of
ARHGAP25 to neutrophils. Significantly reduced ERK1/2, MAPK, and I-κB protein signals
were detected in the arthritic KO mouse ankles.Our findings suggest that ARHGAP25
has a key role in the pathomechanism of autoantibody-induced arthritis in which it
regulates inflammation via the I-κB/NF-κB/IL-1β axis with the involvement of both
immune cells and fibroblast-like synoviocytes.
