Tim4 deficiency reduces CD301b+macrophage and aggravates periodontitis bone loss

Periodontitis is a common chronic inflammatory disease that causes the periodontal bone destruction and may ultimately result in tooth loss.With the progression of periodontitis,the osteoimmunology microenvironment in periodontitis is damaged and leads to the formation of pathological alveolar bone resorption.CD301b^(+)macrophages are specific to the osteoimmunology microenvironment,and are emerging as vital booster for conducting bone regeneration.However,the key upstream targets of CD301b^(+)macrophages and their potential mechanism in periodontitis remain elusive.In this study,we concentrated on the role of Tim4,a latent upstream regulator of CD301b^(+)macrophages.We first demonstrated that the transcription level of Timd4(gene name of Tim4)in CD301b^(+)macrophages was significantly upregulated compared to CD301b^(-) macrophages via high-throughput RNA sequencing.Moreover,several Tim4-related functions such as apoptotic cell clearance,phagocytosis and engulfment were positively regulated by CD301b^(+)macrophages.The single-cell RNA sequencing analysis subsequently discovered that Cd301b and Timd4 were specifically co-expressed in macrophages.The following flow cytometric analysis indicated that Tim4 positive expression rates in total macrophages shared highly synchronized dynamic changes with the proportions of CD301b^(+)macrophages as periodontitis progressed.Furthermore,the deficiency of Tim4 in mice decreased CD301b^(+)macrophages and eventually magnified alveolar bone resorption in periodontitis.Additionally,Tim4 controlled the p38 MAPK signaling pathway to ultimately mediate CD301b^(+)macrophages phenotype.In a word,Tim4 might regulate CD301b^(+)macrophages through p38 MAPK signaling pathway in periodontitis,which provided new insights into periodontitis immunoregulation as well as help to develop innovative therapeutic targets and treatment strategies for periodontitis.

CD301b^(+) macrophages mediate angiogenesis of calcium phosphate bioceramics by CaN/NFATc1/VEGF axis

Calcium phosphate(CaP)bioceramics are important for tissue regeneration and immune response,yet how CaP bioceramics influence these biological processes remains unclear.Recently,the role of immune cells in biomaterial-mediated regeneration,especially macrophages,has been well concerned.CD301b^(+)macrophages were a new subset of macrophages we have discovered,which were required for bioceramics-mediated bone regeneration.Nevertheless,the impact of CD301b^(+)macrophages on angiogenesis,which is a vital prerequisite to bone formation is yet indistinct.Herein,we found that CD301b^(+)macrophages were closely correlated to angiogenesis of CaP bioceramics.Additionally,depletion of CD301b^(+)macrophages led to the failure of angiogenesis.We showed that store-operated Ca^(2+)entry and calcineurin signals regulated the VEGF expression of CD301b^(+)macrophages via the NFATc1/VEGF axis.Inhibition of calcineurin effectively impaired angiogenesis via decreasing the infiltration of CD301b^(+)macrophages.These findings provided a potential immunomodulatory strategy to optimize the integration of angiogenesis and bone tissue engineering scaffold materials.