Gelsolin alleviates rheumatoid arthritis by negatively regulating NLRP3 inflammasome activation.

Despite numerous biomarkers being proposed for rheumatoid arthritis (RA), a gap remains in our understanding of their mechanisms of action. In this study, we discovered a novel role for gelsolin (GSN), an actin-binding protein whose levels are notably reduced in the plasma of RA patients. We elucidated that GSN is a key regulator of NLRP3 inflammasome activation in macrophages, providing a plausible explanation for the decreased secretion of GSN in RA patients. We found that GSN interacts with NLRP3 in LPS-primed macrophages, hence modulating the formation of the NLRP3 inflammasome complex. Reducing GSN expression significantly enhanced NLRP3 inflammasome activation. GSN impeded NLRP3 translocation to the mitochondria; it contributed to the maintenance of intracellular calcium equilibrium and mitochondrial stability. This maintenance is crucial for controlling the inflammatory response associated with RA. Furthermore, the exacerbation of arthritic symptoms in GSN-deficient mice indicates the potential of GSN as both a diagnostic biomarker and a therapeutic target. Moreover, not limited to RA models, GSN has demonstrated a protective function in diverse disease models associated with the NLRP3 inflammasome. Myeloid cell-specific GSN-knockout mice exhibited aggravated inflammatory responses in models of MSU-induced peritonitis, folic acid-induced acute tubular necrosis, and LPS-induced sepsis. These findings suggest novel therapeutic approaches that modulate GSN activity, offering promise for more effective management of RA and a broader spectrum of inflammatory conditions.

Infantile Hemangiomas Cleared by Combined Therapy With Pulsed Dye Laser and Propranolol.

BACKGROUND: Oral propranolol is the first-line therapy for infantile hemangioma. Combining it with pulse dye laser (PDL) (595nm-long PDL) could reduce treatment duration and sequelae incidence and severity. OBJECTIVE: To determine the effect of PDL-propranolol treatment on duration to cure and sequelae. METHODS: All consecutive patients with infantile hemangioma who were cured by PDL-propranolol treatment were identified. RESULTS: In the 27 cases, average age at treatment start was 4.3 ± 3.8 months, mean tumor diameter was 11.1 ± 14.0 cm2, and tumor-type was most common (72.4% of lesions). The patients received 9.8 ± 10.5 PDL sessions. After ensuring patients had no physical contraindications, including heart disease, oral propranolol was started at 1 mg/kg/d, increased up to 3 mg/kg/d as a maintenance dose. Mean propranolol treatment duration was 11.1 ± 4.9 months. Total treatment duration was 15.3 ± 10.8 months. CONCLUSION: Our data in the context of recent literature suggest combining propranolol with PDL may reduce propranolol duration without increasing harms.

Sphingosine-1-Phosphate Facilitates Skin Wound Healing by Increasing Angiogenesis and Inflammatory Cell Recruitment with Less Scar Formation.

Wound healing starts with the recruitment of inflammatory cells that secrete wound-related factors. This step is followed by fibroblast activation and tissue construction. Sphingosine-1-phosphate (S1P) is a lipid mediator that promotes angiogenesis, cell proliferation, and attracts immune cells. We investigated the roles of S1P in skin wound healing by altering the expression of its biogenic enzyme, sphingosine kinase-1 (SphK1). The murine excisional wound splinting model was used. Sphingosine kinase-1 (SphK1) was highly expressed in murine wounds and that SphK1-/- mice exhibit delayed wound closure along with less angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. The SphK1 overexpression also led to less scarring, and the interaction between transforming growth factor (TGF)-ß1 and S1P receptor-2 (S1PR2) signaling is likely to play a key role. In summary, SphK1 play important roles to strengthen immunity, and contributes early wound healing with suppressed scarring. S1P can be a novel therapeutic molecule with anti-scarring effect in surgical, trauma, and chronic wound management.