Lacking ARHGAP25 mitigates the symptoms of autoantibody-induced arthritis in mice.

Objective: 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. Methods: 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. Results: In the absence of ARHGAP25, the severity of inflammation, joint destruction, and mechanical hyperalgesia significantly decreased, similarly to phagocyte infiltration, IL-1ß, 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. Conclusion: 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-1ß axis with the involvement of both immune cells and fibroblast-like synoviocytes.

Association of Social Jetlag With Sleep Quality and Autonomic Cardiac Control During Sleep in Young Healthy Men.

Social jetlag (SJL), the difference in sleep timing between work and free days is a consequence of the discrepancy between the individual's circadian rhythm and the social clock. SJL is considered a chronic stress factor and has been linked to various health problems. In this field study, we examined for the first time the association between SJL and cardiac regulation during sleep. 33 healthy young men aged 20-26 years participated in the study. The median SJL was used as a cut-off value to assign the participants into two groups with either lower or higher SJL. As a marker of autonomic control we analyzed heart rate variability (HRV) and addressed intra-individual differences between workdays and free days. In subjects with higher SJL, pNN50, an indicator of vagal activity was lower in the first 3 h of sleep on workday as compared to free day (day × sleep block × group, p = 0.015), indicating a more adaptable regulation on free days, when subjects slept according to their own preference. However, in subjects with lower SJL, no HRV differences were found between the two nights. SJL showed correlation with the free day-workday differences of both pNN50 and another vagal index, RMSSD in the first 2 h of sleep (p = 0.023 and 0.047, respectively). In subjects with higher SJL, a different HF power on workdays and free days (p = 0.031) also indicated that a shift in sleep timing is accompanied by an altered parasympathetic activity in the first few hours of sleep. Furthermore, subjective sleep quality on workdays was negatively associated with SJL (p = 0.02), and subjects with higher SJL reported worse sleep quality on workday than on free day (p = 0.027). Taken together, our data call attention on the potential effect of SJL on sleep quality and vagal activity during sleep.