Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macr...Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity,which leads to microflora disturbance,destructive periodontal inflammation and alveolar bone loss eventually.Here,an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages(named ex-situ macrophages hereafter)and a complement C5a receptor antagonist(C5A)to the gingival crevice.Through appropriately tuning the hydrogel stiffness,the phagocytic activity of these macrophages is greatly enhanced,reaching an optimal performance at the elastic modulus of 106 kPa.Meanwhile,C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages.Besides,the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche,which contributes to the alleviated periodontal inflammation and attenuated bone loss as well.This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells,which is expected to find wide applications even beyond periodontitis treatment.展开更多
The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is...The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is also a critical component of innate immunity. While complement is known to interact with TLR-mediated signals, the interactions between NOD-like receptors and complement are not well understood. Here we report a synergistic interaction between C5a and Nod2 signaling in RAW 264.7 marophages. Long-term treatment with muramyl dipeptide (MDP), a NOD2 ligand, enhanced C5a-mediated expression of chemokine mRNAs in RAW 264.7 cells. This response was dependent on NOD2 expression and was associated with a decrease in expression of C5L2, a receptor for C5a which acts as a negative modulator of C5a receptor (C5aR) activity. MDP amplified C5a-mediated phosphorylation of p38 MAPK. Treatment of RAW264.7 cells with an inhibitor of p38 attenuated the synergistic effects of C5aon MDP-primed cells on MIP-2, but not MCP-1, mRNA. In contrast, inhibition of AKT prevented C5a stimulation of MCP-1, but not MIP-2, mRNA, in MDP-primed cells. Taken together, these data demonstrated a synergistic interaction between C5a and NOD2 in the regulation of chemokine expression in macrophages, associated with a down-regulation of C5L2, a negative regulator of C5a receptor activity.展开更多
The process of apoptotic cell death for maintenance of cell homeostasis is now believed to be flexible. To examine the mechanism for this flexibility, the process of programmed cell death is sometimes divided into thr...The process of apoptotic cell death for maintenance of cell homeostasis is now believed to be flexible. To examine the mechanism for this flexibility, the process of programmed cell death is sometimes divided into three phases: initiation, effector and execution. We have demonstrated that apoptotic cells commonly express a de novo synthesized C5a receptor (C5aR), which belongs to the G protein-coupled receptor (GPCR) family. A natural agnostic ligand of the C5aR, C5a, is produced from plasma C5 by C5 convertase in the early phase of acute inflammation. Although it is not realistic, we found that C5a can adjust apoptotic cell lifespan long. We recently have read interesting reports that apoptotic cells can release natural agnostic ligands at the initiation phase and corresponding GPCRs are already expressed on cell surfaces of apoptotic cells. Conversely, we found that apoptotic cells commonly release an alternative antagonistic/agnostic ligand of the de novo synthesized C5aR, ribosomal protein S19 (RP S19) polymer. The RP S19 polymer can adjust apoptotic cell lifespan short. Importantly, the C5a-dependent regulation is limited by the C5aR sensitization, but the RP S19 polymer-dependent regulation is unlimited by the C5aR desensitization. Therefore, we suggested that apoptotic cells commonly release agnostic ligands in the initiation phase that should lengthen intermittently a period of the initiation phase. Next, apoptotic cells commonly release antagonistic/agnostic ligands in the effector phase that should continue shortening a period of the effector phase. In addition, we know that an inherited erythroblastopenia is associated with mutations in the RP S19 gene. However, the roles of RP S19 in the formation of erythroblast-macrophage islands are not clearly understood. We recently have found that a different arm that the RP S19 polymer has connects the de novo synthesized C5aR on erythroblasts and the generally expressed C5aR on macrophages. Therefore, we suggested that apoptotic cells commonly release antagoni展开更多
基金This work was supported by the National Natural Science Foundation of China(82170987,81970963,51933011,31971296)the Natural Science Foundation of Guangdong Province(2021A1515012535)the General Scientific Research Cultivation Project of Guanghua School of Stomatology,Sun Yat-Sen University(174-2018-XMZC-0001-03-0125/D-16).
文摘Periodontitis is admittedly a microbe-driven intractable infectious disease,in which Porphyromonas gingivalis(Pg)plays a keystone role.Pg can selectively impair the antimicrobial responses of periodontal resident macrophages including their phagocytic and bactericidal activity without interfering their proinflammatory activity,which leads to microflora disturbance,destructive periodontal inflammation and alveolar bone loss eventually.Here,an injectable ROS-sensitive hydrogel is developed for releasing active bone marrow-derived macrophages(named ex-situ macrophages hereafter)and a complement C5a receptor antagonist(C5A)to the gingival crevice.Through appropriately tuning the hydrogel stiffness,the phagocytic activity of these macrophages is greatly enhanced,reaching an optimal performance at the elastic modulus of 106 kPa.Meanwhile,C5A avoids undesired C5a receptor activation by Pg to ensure the bacterial killing activity of both the ex-situ and in-situ macrophages.Besides,the ROS-sensitive hydrogels show another distinct feature of decreasing the ROS level in periodontal niche,which contributes to the alleviated periodontal inflammation and attenuated bone loss as well.This study highlights the potential of utilizing hydrogels with tailored biomechanical properties to remodel the functions of therapeutic cells,which is expected to find wide applications even beyond periodontitis treatment.
文摘The innate immune response is a complex process involving multiple pathogen-recognition receptors, including toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors. Complement is also a critical component of innate immunity. While complement is known to interact with TLR-mediated signals, the interactions between NOD-like receptors and complement are not well understood. Here we report a synergistic interaction between C5a and Nod2 signaling in RAW 264.7 marophages. Long-term treatment with muramyl dipeptide (MDP), a NOD2 ligand, enhanced C5a-mediated expression of chemokine mRNAs in RAW 264.7 cells. This response was dependent on NOD2 expression and was associated with a decrease in expression of C5L2, a receptor for C5a which acts as a negative modulator of C5a receptor (C5aR) activity. MDP amplified C5a-mediated phosphorylation of p38 MAPK. Treatment of RAW264.7 cells with an inhibitor of p38 attenuated the synergistic effects of C5aon MDP-primed cells on MIP-2, but not MCP-1, mRNA. In contrast, inhibition of AKT prevented C5a stimulation of MCP-1, but not MIP-2, mRNA, in MDP-primed cells. Taken together, these data demonstrated a synergistic interaction between C5a and NOD2 in the regulation of chemokine expression in macrophages, associated with a down-regulation of C5L2, a negative regulator of C5a receptor activity.
文摘The process of apoptotic cell death for maintenance of cell homeostasis is now believed to be flexible. To examine the mechanism for this flexibility, the process of programmed cell death is sometimes divided into three phases: initiation, effector and execution. We have demonstrated that apoptotic cells commonly express a de novo synthesized C5a receptor (C5aR), which belongs to the G protein-coupled receptor (GPCR) family. A natural agnostic ligand of the C5aR, C5a, is produced from plasma C5 by C5 convertase in the early phase of acute inflammation. Although it is not realistic, we found that C5a can adjust apoptotic cell lifespan long. We recently have read interesting reports that apoptotic cells can release natural agnostic ligands at the initiation phase and corresponding GPCRs are already expressed on cell surfaces of apoptotic cells. Conversely, we found that apoptotic cells commonly release an alternative antagonistic/agnostic ligand of the de novo synthesized C5aR, ribosomal protein S19 (RP S19) polymer. The RP S19 polymer can adjust apoptotic cell lifespan short. Importantly, the C5a-dependent regulation is limited by the C5aR sensitization, but the RP S19 polymer-dependent regulation is unlimited by the C5aR desensitization. Therefore, we suggested that apoptotic cells commonly release agnostic ligands in the initiation phase that should lengthen intermittently a period of the initiation phase. Next, apoptotic cells commonly release antagonistic/agnostic ligands in the effector phase that should continue shortening a period of the effector phase. In addition, we know that an inherited erythroblastopenia is associated with mutations in the RP S19 gene. However, the roles of RP S19 in the formation of erythroblast-macrophage islands are not clearly understood. We recently have found that a different arm that the RP S19 polymer has connects the de novo synthesized C5aR on erythroblasts and the generally expressed C5aR on macrophages. Therefore, we suggested that apoptotic cells commonly release antagoni
