Search

Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal DNase2a activate a DNA-PKcs-mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression. In the dexamethasone-thymus model, hematopoietic Rictor deletion blocked efferocytosing macrophage proliferation, apoptotic cell clearance, and tissue resolution. In atherosclerosis regression, silencing macrophage Rictor or DNase2a blocked efferocyte proliferation, apoptotic cell clearance, and plaque stabilization. In view of previous work showing that other types of apoptotic cell cargo can promote resolution in individual efferocytosing macrophages, the findings here suggest that signaling-triggered apoptotic cell-derived nucleotides can amplify this benefit by increasing the number of these macrophages., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The regeneration of lost periodontal apparatus in periodontitis treatment remains a clinical challenge due to the limited regenerative capacity of cementum, periodontal ligament and alveolar bone in periodontitis condition. For periodontal tissue regeneration, it is essential to regulate the inflammatory response and the subsequent differentiation of periodontal cells under the condition due to the infectious nature of the disease. In this study, it was noted that 45 nm gold nanoparticles (AuNPs) could exhibit significant anti-inflammatory effect and improve the periodontal inflammatory microenvironment via regulating inflammatory and regenerative cytokine production and modulating macrophage polarization, subsequently affect the differentiation of human periodontal ligament cells (hPDLCs). With the addition of direct effects of AuNPs on hPDLCs, the periodontal tissue differentiation capacity of hPDLCs in LPS-activated inflammatory macrophage-hPDLCs coculture system was significantly enhanced by the interaction between AuNPs-conditioned macrophage and AuNPs-stimulated hPDLCs. The potential therapeutic application of AuNPs in periodontal tissue regeneration and periodontitis treatment was investigated using both rat fenestration and ligature-induced periodontitis models. It was found that the treatment of 45 AuNPs showed significantly increased newly-formed periodontal attachment, bone and cementum in periodontal defect and less tissue destruction in the progression of periodontitis. This study demonstrated that 45 nm AuNPs could not only directly modulate hPDLCs, but also regulate the early inflammatory response of periodontal tissues via the regulation of macrophage phenotypes, therefore, generate a microenvironment with constraint inflammatory cytokine levels and reparative cytokines such as bone morphogenetic protein-2 (BMP-2), leading to PDLC differentiation, periodontal tissue regeneration and the prevention of periodontitis progression., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tumor‐associated macrophages (TAMs) play a critical role in the immunosuppressive solid tumor microenvironment (TME), yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significant challenge in translational immuno‐oncology. Here, we report an innovative nanodrug‐delivering‐drug (STNSP@ELE) strategy that leverages two‐dimensional (2D) stanene‐based nanosheets (STNSP) and β‐Elemene (ELE), a small‐molecule anticancer drug, to overcome TAM‐mediated immunosuppression and improve chemo‐immunotherapy. Our results demonstrate that both STNSP and ELE are capable of polarizing the tumor‐supportive M2‐like TAMs into a tumor‐suppressive M1‐like phenotype, which acts with the ELE chemotherapeutic to boost antitumor responses. In vivo mouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantly increasing the intratumoral ratio of M1/M2‐like TAMs, enhancing the population of CD4+ and CD8+ T lymphocytes and mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, thereby promoting a robust antitumor response. Our study not only demonstrates that the STNSP@ELE chemo‐immunotherapeutic nanoplatform has immune‐modulatory capabilities that can overcome TAM‐mediated immunosuppression in solid tumors, but also highlights the promise of this nanodrug‐delivering‐drug strategy in developing other nano‐immunotherapeutics and treating various types of immunosuppressive tumors. [ABSTRACT FROM AUTHOR]

Perturbing plaque macrophages: Macrophages in atherosclerotic lesions promote inflammation and plaque progression and are an attractive therapeutic target. Here, Tao et al. used nanoparticles to inhibit pro-atherogenic macrophages by siRNA targeting Ca2+/calmodulin-dependent protein kinase γ. Nanoparticle treatment induced phagocytosis of apoptotic cells in plaques and promoted plaque stability, reducing necrotic area and increasing fibrous cap thickness in a mouse model of atherosclerosis. This study establishes proof of concept for siRNA nanoparticles targeting lesional macrophages as a treatment for atherosclerosis. Atherosclerotic lesional macrophages express molecules that promote plaque progression, but lack of mechanisms to therapeutically target these molecules represents a major gap in translational cardiovascular research. Here, we tested the efficacy of a small interfering RNA (siRNA) nanoparticle (NP) platform targeting a plaque-destabilizing macrophage molecule—Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ). CaMKIIγ becomes activated in advanced human and mouse plaque macrophages and drives plaque necrosis by suppressing the expression of the efferocytosis receptor MerTK. When macrophage-targeted siCamk2g NPs were administered to Western diet–fed Ldlr−/− mice, the atherosclerotic lesions showed decreased CaMKIIγ and increased MerTK expression in macrophages, improved phagocytosis of apoptotic cells (efferocytosis), decreased necrotic core area, and increased fibrous cap thickness—all signs of increased plaque stability—compared with mice treated with control siRNA NPs. These findings demonstrate that atherosclerosis-promoting genes in plaque macrophages can be targeted with siRNA NPs in a preclinical model of advanced atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate if the expression and chemotactic activity of RANTES are different in IL-1β treated autologous eutopic endometrial stromal cells compared to ectopic and normal endometrium. Study design: Conditioned media from IL-1β-treated ectopic, autologous eutopic and normal endometrial stromal cells were analyzed with a specific sandwich ELISA to quantify RANTES. The monocyte chemotactic activity of RANTES was assayed in a Boyden Chamber. Results: RANTES expression in IL-1β-treated autologous eutopic and normal endometrial stromal cells was significantly lower than ectopic endometrium. Autologous eutopic endometrial stromal cells showed a significant increase in RANTES expression compared to normal endometrium after IL-1β stimulation for 60h. The monocyte chemotactic activities of these conditioned media were highly correlated with the immunoreactive RANTES concentration. We observed significantly increased monocyte chemotactic activity in conditioned media of ectopic stromal cells compared to autologous eutopic and normal endometrium. The different chemotactic activity of RANTES between the autologous eutopic and normal endometrial stromal cells was also statistically significant. RANTES accounts for the majority (62%) of the monocyte chemotactic activity in ectopic endometrial stromal cells conditioned media and 55% of that activity in autologous eutopic endometrium. Conclusions: Although the eutopic endometric of women with and without endometriosis are histologically similar, our findings confirm that different expression and chemotactic activity of RANTES exist between autologous eutopic and normal endometrium. The altered expression of RANTES and monocyte chemotactic activity observed in ectopic, autologous eutopic and normal endometrium suggest the autologous eutopic endometrium may contribute to the pathogenesis of endometriosis. [Copyright &y& Elsevier]