Stattic

This study investigates the therapeutic effects of recombinant human IL-10 (rhIL-10) administered via aerosol inhalation in acute lung injury (ALI), with a particular focus on neutrophils. It explores how rhIL-10, in the presence of platelets, modulates neutrophil polarization to ameliorate acute lung injury. Initially, the ALI model established in mice demonstrated that aerosol inhalation of rhIL-10 significantly mitigated the cytokine storm in the lungs, reduced pulmonary edema, and alleviated histopathological damage to lung tissue. Additionally, rhIL-10 administration was found to decrease neutrophil infiltration and platelet activation in the lungs of mice, inhibiting the formation of platelet-neutrophil aggregates (PNAs) and promoting the differentiation of neutrophils toward an anti-inflammatory phenotype in the presence of platelets. Subsequently, primary neutrophils and platelets were isolated from mouse bone marrow and blood to explore the underlying mechanisms. The results indicated that rhIL-10 promotes the expression of the signal transducer and activator of transcription 3 (STAT3) and the suppressor of cytokine signaling 3 (SOCS3) in neutrophils while inhibiting the activation of the nuclear factor kappa B (NF-κB) and the NF-κB inhibitor (IκB), which in turn enhances CD40 expression. This interaction facilitates the formation of PNAs and influences neutrophil phenotype differentiation. Furthermore, the application of the STAT3 phosphorylation inhibitor Stattic and CD40 antibody in vivo provided further validation of this potential mechanism. In conclusion, these results indicate that aerosol inhalation of rhIL-10 effectively ameliorates ALI. The underlying mechanism may involve the modulation of the neutrophil STAT/SOCS-IκB/NF-κB-CD40 signaling pathway, promoting interactions between neutrophils and platelets that facilitate the differentiation of neutrophils toward an anti-inflammatory phenotype.

Perioperative Neurocognitive Disorders (PND) are associated withanesthesia and surgery, especially in the elderly. Astrocyte activation in old mice correlates with PND development. These cells can switch to a pro-inflammatory or an anti-inflammatory phenotype, regulated by the STAT3 pathway. It remains unclear whether STAT3 can alleviate PND symptoms in elderly mice by modulating the transitions between these astrocyte phenotypes.

Senescence was induced in eight-week-old male C57BL/6J mice with D-galactose, followed by tibial fracture surgery under anesthesia to model PND. On the third postoperative day, cognitive function was assessed using fear conditioning, synaptic plasticity using Golgi/ electrophysiology, and astrocyte phenotype /STAT3/pSTAT3(phosphorylated STAT3) using Western blot/immunofluorescence. The content of neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), was also measured. Primary astrocytes were stimulated with the conditioned medium referred to as ACM to induce pro-inflammatory reactive astrocytes. Stattic, an inhibitor of STAT3 phosphorylation, was used to investigate its effects on astrocyte phenotypic transformation and hippocampus-dependent learning and memory in aging mice, both in vitro and in vivo.

On the third postoperative day, pSTAT3 levels and pro-inflammatory astrocytes increased in the hippocampal CA1 region, with no change in total STAT3 or anti-inflammatory astrocytes, accompanied by a decrease in GDNF and BDNF.ACM treatment of primary astrocytes promoted pro-inflammatory phenotype conversion, which was inhibited by stattic without affecting anti-inflammatory phenotype. Intraperitoneal injection of stattic in mice reduced the accumulation of pro-inflammatory astrocytes, increased the levels of BDNF and GDNF, enhanced synaptic plasticity, and improved hippocampus-dependent learning and memory functions in anesthesia-induced senescent mice, without altering anti-inflammatory astrocytes.

Inhibiting STAT3 phosphorylation may improve synaptic plasticity in the CA1 region of the hippocampus by modulating pro-inflammatory astrocytes, thereby alleviating perioperative neurocognitive dysfunction in D-galactose-induced aging mice.