Lithium Promotes Osteogenesis via Rab11a-Facilitated Exosomal Wnt10a Secretion and ß-Catenin Signaling Activation.

Both bone mesenchymal stem cells (BMSCs) and their exosomes suggest promising therapeutic tools for bone regeneration. Lithium has been reported to regulate BMSC function and engineer exosomes to improve bone regeneration in patients with glucocorticoid-induced osteonecrosis of the femoral head. However, the mechanisms by which lithium promotes osteogenesis have not been elucidated. Here, we demonstrated that lithium promotes the osteogenesis of BMSCs via lithium-induced increases in the secretion of exosomal Wnt10a to activate Wnt/ß-catenin signaling, whose secretion is correlated with enhanced MARK2 activation to increase the trafficking of the Rab11a and Rab11FIP1 complexes together with exosomal Wnt10a to the plasma membrane. Then, we compared the proosteogenic effects of exosomes derived from lithium-treated or untreated BMSCs (Li-Exo or Con-Exo) both in vitro and in vivo. We found that, compared with Con-Exo, Li-Exo had superior abilities to promote the uptake and osteogenic differentiation of BMSCs. To optimize the in vivo application of these hydrogels, we fabricated Li-Exo-functionalized gelatin methacrylate (GelMA) hydrogels, which are more effective at promoting osteogenesis and bone repair than Con-Exo. Collectively, these findings demonstrate the mechanism by which lithium promotes osteogenesis and the great promise of lithium for engineering BMSCs and their exosomes for bone regeneration, warranting further exploration in clinical practice.

ZAP facilitates NLRP3 inflammasome activation via promoting the oligomerization of NLRP3.

The NOD-like receptor family protein 3 (NLRP3) inflammasome is a crucial complex for the host to establish inflammatory immune responses and plays vital roles in a series of disorders, including Alzheimer's disease and acute peritonitis. However, its regulatory mechanism remains largely unclear. Zinc finger antiviral protein (ZAP), also known as zinc finger CCCH-type antiviral protein 1 (ZC3HAV1), promotes viral RNA degradation and plays vital roles in host antiviral immune responses. However, the role of ZAP in inflammation, especially in NLRP3 activation, is unclear. Here, we show that ZAP interacts with NLRP3 and promotes NLRP3 oligomerization, thus facilitating NLRP3 inflammasome activation in peritoneal macrophages of C57BL/6 mice. The shorter isoform of ZAP (ZAPS) appears to play a greater role than the full-length isoform (ZAPL) in HEK293T cells. Congruously, Zap-deficient C57BL/6 mice may be less susceptible to alum-induced peritonitis and lipopolysaccharide-induced sepsis in vivo. Therefore, we propose that ZAP is a positive regulator of NLRP3 activation and a potential therapeutic target for NLRP3-related inflammatory disorders.

Exploring the immunological landscape of osteomyelitis through mendelian randomization analysis.

Background: Osteomyelitis is a severe bone marrow infection, whose pathogenesis is not yet fully understood. This study aims to explore the causal relationship between immune cell characteristics and osteomyelitis, hoping to provide new insights for the prevention and treatment of osteomyelitis. Methods: Based on two independent samples, this study employed a two-sample Mendelian randomization (MR) analysis to assess the causal relationship between 731 immune cell characteristics (divided into seven groups) and osteomyelitis. Genetic variants were used as proxies for risk factors to ensure that the selected instrumental variables meet the three key assumptions of MR analysis. Genome-Wide Association Studies (GWAS) data for immune characteristics were obtained from the public GWAS catalog, while data for osteomyelitis was sourced from the FinnGen. Results: At a significance level of 0.05, 21 immune phenotypes were identified as having a causal relationship with osteomyelitis development. In the B cell group, phenotypes such as Memory B cell % B cell (percentage of memory B cells within the total B cell population, % finger cell ratio), CD20- %B cell (percentage of B cells that do not express the CD20 marker on their surface), and Memory B cell % lymphocyte showed a positive causal relationship with osteomyelitis, while Naive-mature B cell %B cell and IgD-CD38-absolute cell counts (AC) phenotypes showed a negative causal relationship. In addition, specific immune phenotypes in the conventional dendritic cells (cDCs) group, Myeloid cell group, TBNK (T cells, B cells, natural killer cells) cell group, T cell maturation stage, and Treg cell group also showed significant associations with osteomyelitis. Through reverse MR analysis, it was found that osteomyelitis had no significant causal impact on these immune phenotypes, suggesting that the occurrence of osteomyelitis may not affect these immune cell phenotypes. Conclusion: To our knowledge, this is the first study to shed light on the causal relationship between specific immune cell characteristics and the development of osteomyelitis, thereby providing a new perspective to understand the immune mechanism of osteomyelitis. These findings are significant for formulating targeted prevention and treatment strategies, and hold promise to improve the treatment outcomes for patients with osteomyelitis.