Engineering of cell surfaces holds promise in manipulating cellular activities in a physicochemical route as a complement to the biological approach. Mediated by Ca2+, a quick and convenient yet cytocompatible method is used to achieve surface engineering, by which polydopamine nanostructures can be in situ grown onto dendritic cell (DC) surfaces within 10 min. Ca2+, as the physical bridge between the negative cell surface and polydopamine, avoids the direct chemical polymerization of polydopamine onto the cell surface, critically important to maintain the cell viability. As a proof of concept in potential applications, this cell surface engineering shows a good control toward DC maturation. Upon surface polydopamine engineering, bone-marrow-derived DC exhibits a unique bidirectional control of maturation. The polydopamine structure enables effective suppression of DC activation by acting as an efficient scavenger of reactive oxygen species, a key signal during maturation. Conversely, an 808 nm laser irradiation can remotely relieve the suppressed state and effectively activate DC maturation by the photoheat effect of polydopamine (39 °C). The work provides an easily implemented, straightforward approach to achieve cell surface engineering, through which the DC maturation can be controlled.
Reactive oxygen species (ROS)-responsive nanomedicine has been extensively developed to improve the therapeutic effects while reducing the systemic toxicity. ROS, as important biological metabolites and signaling molecules, are known to overexpress in most of tumors and inflammations. Among various ROS-sensitive moieties, phenylborate ester (PBAE) with easy modifiable structure and excellent biocompatibility, represents one of the most ROS-sensitive structures. To harness it as a switch, the past several years had witnessed a booming of ROS-sensitive PBAE-based nanomedicine for various medical purposes. Much of the efforts were devoted to exploiting the potential in the management of antitumor and anti-inflammation. This review first summarizes the design strategies of PBAE in the construction of nanomedicine, with PBAE acting as not only the ROS-responsive unit, but also the roles of hydrophobic backbone or bridging segment in the macromolecular structures. The ROS-responsive mechanisms are then briefly discussed. Afterward, we focus on the introduction of the state-of-the-art research on ROS-responsive PBAE-based nanomedicine for antitumor and anti-inflammation applications. The conclusion and future perspectives of ROS-responsive nanomedicine are also provided.
Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder with a heterogeneous clinical manifestations that results from abundant immunological abnormalities. Innate lymphoid cells (ILCs), one subset of the innate immune cells, are divided into cytotoxic ILCs (namely natural killer cells) and non-cytotoxic ILCs (namely helper-ILCs). Non-cytotoxic ILCs are composed of three groups, group 1 ILCs, group 2 ILCs and group 3 ILCs, based on depended transcription factors and producing cytokines. So far, alterations of ILCs and their subsets have been reported in some autoimmune diseases except SLE.
Objectives
To visualise differences in frequencies of ILCs and their subsets in the peripheral blood of patients with SLE and healthy controls in Chinese Han population.
Methods
Peripheral blood mononuclear cells (PBMCs) was obtained from twenty-five SLE patients and twelve healthy controls and were stained with antibodies to CD45, lineage (CD3, CD19, CD123, CD11c, CD14, CD16, CD34, CD94, and FcεRIα), CD4, CD8, CD127, CD117, CRTH2 and NKp44. Circulating total ILCs and its subsets were identified by flow cytometry. The associations between disease activity and all the detected cells were evaluated using the Pearson or Spearman correlation coefficient.
Results
Increased frequencies of ILC2 and ILC3 were observed in patients compared to controls, while decreased frequency of ILC1 was found in patients compared with controls (p=0.008, p=0.004, and p=0.006, respectively). We also found the expression of T cell surface markers, CD4 or CD8, on ILCs and their subsets. The results showed that decreased frequencies of CD4+CD8+ ILCs, CD4+CD8-ILC1, CD4+CD8+ ILC2, CD4+CD8- ILC2, and CD4+CD8-CD336- ILC3 were found in patients compared with healthy controls (p=0.001, p=0.017, p=0.001, p=0.004, and p=0.002, respectively). Furthermore, frequencies of CD4+CD8+ ILCs and CD4+CD8+ ILC2 were positively correlated with the SLEDAI-2000 score (r=−0.548, p=0.005 and r=−0.613, p=0.001, respectively). Frequencies of CD4-CD8+ ILCs and CD4-CD8+ ILC1 were positively related with serum C3 level (r=0.519, p=0.008 and r=0.528, p=0.007, respectively), and were positively related with serum C4 level (r=0.623, p=0.001 and r=0.643, p=0.001, respectively).
Conclusions
In the present study, we demonstrated that frequencies of circulating ILCs and its subsets were altered in SLE patients and some subpopulations were negatively correlated with SLE disease activity.
References
[1] Shikhagaie MM, Germar K, Bal SM, Ros XR, Spits H. Innate lymphoid cells in autoimmunity: emerging regulators in rheumatic diseases. Nature reviews. Rheumatology2017;13:164–173. doi:10.1038/nrrheum.2016.218 [2] Morel L. Immunometabolism in systemic lupus erythematosus. Nature reviews Rheumatology2017;13:280–290. doi:10.1038/nrrheum.2017.43
Protection of cardiomyocytes against oxidative stress is vital to alleviate myocardial ischemia/reperfusion injury (MI/RI). However, antioxidative treatment is hampered by the lack of safe and effective therapeutics. Polydopamine (PDA), as a biodegradable class of nanomaterial with excellent antioxidant properties, has shown great potential in treating MI/RI. To achieve site-specific antioxidative efficacy, we established a PDA-based biomimetic nanoplatform (PDA@M), which consisted of a polydopamine core and a macrophage membrane shell to form a shell–core structure. By inheriting the inherent migration capability of macrophages, PDA@M was able to target the infarcted myocardium and exert an antioxidative effect to protect the myocardium. The results demonstrated that the accumulation of the membrane-wrapped nanoparticles (NPs) in the infarcted myocardium was greatly increased as compared with PDA alone, which effectively relieved the MI/RI-induced oxidative stress. PDA@M largely decreased the infarct size and improved the cardiac function post-MI/RI. Our study revealed that PDA@M could inhibit cell pyroptosis by suppressing the NLRP3/caspase-1 pathway, which is known to play a significant role in the antioxidant signaling pathway. In summary, PDA@M can target the infarcted myocardium and exert antioxidative and antipyroptosis functions to protect the myocardium against MI/RI-induced oxidative stress, suggesting that it may prove to be a potential therapeutic agent for MI/RI.
Due to unsatisfactory tumor-targeting efficiency, hitch-hiking nanomedicines with tumor "smelling" immune cells have rapidly evolved to achieve a more precision delivery. However, the current research tends to default to the smelling capacity of neutrophils and largely overlooks the capacity of those immune cells that are heavily dependent on the pathogen exposure history of individuals. By avoiding risky strategies, such as altering the housing environment of mice for the improved activity of immune cells, we propose a new concept of nano-immunotraining strategy to quickly activate neutrophil tumor tropism and thereby give an enhanced tumor-targeting capacity. Such a strategy involves a facile construction of a vaccine-like nano-CpG adjuvant, followed by pre-immunizing on mice periodically to mimic the pathogen exposure. The results demonstrated that a significantly enhanced tumor-targeting accumulation of neutrophils harvested from nano-immunotrained mice could be achieved, either by intraperitoneal or intravenous injection. This easily accessed, reproducible, and biosafe nano-immunotraining strategy holds a great promise for more precision delivery of nanomedicines.
Severe inflammation, progressive cartilage, and bone destruction are typical pathologic changes in temporomandibular joint (TMJ) arthritis and lead to great difficulty for treatment. However, current therapy is inefficient to improve degenerative changes in progressive TMJ arthritis. This study investigated the therapeutic effects of human dental pulp stem cells (DPSCs) on severe inflammatory TMJ diseases. Progressive TMJ arthritis in rats was induced by intra-articular injection of complete Freund’s adjuvant and monosodium iodoacetate. DPSCs were injected into the articular cavity to treat rat TMJ arthritis, with normal saline injection as control. Measurement of head withdrawal threshold, micro–computed tomography scanning, and histologic staining were applied to evaluate the severity of TMJ arthritis. Results showed that local injection of DPSCs in rats with TMJ arthritis relieved hyperalgesia and synovial inflammation, attenuated cartilage matrix degradation, and induced bone regeneration. Inflammatory factors TNF-α and IFN-γ were elevated in progressive TMJ arthritis and partially decreased by local injection of DPSCs. MMP3 and MMP13 were elevated in the arthritis + normal saline group and decreased in the arthritis + DPSCs group, which indicated amelioration of matrix degradation. The isolated primary synoviocytes were cocultured with DPSCs after inflammatory factors stimulated to explore the possible biological mechanisms. The expression of MMP3 and MMP13 in synoviocytes was elevated after TNF-α and IFN-γ stimulation and partially reversed by DPSC treatment in the in vitro study. The signal transducer and activator of transcription 1 (STAT1) was activated by inflammatory stimulation and suppressed by DPSC coculture. The upregulation of MMP3 and MMP13 triggered by inflammation was blocked by STAT1-specific inhibitor, suggesting that STAT1 regulated the expression of MMP3 and MMP13. In conclusion, this study demonstrated the possible therapeutic effects of local injection of DPSCs on progressive TMJ arthritis by inhibiting the expression of MMP3 and MMP13 through the STAT1 pathway.
Background: The early treatment of rheumatoid arthritis (RA) is associated with better outcomes. In recent years, studies in our understanding of the preclinical events in RA help to define the “at-risk” populations who might go on to develop RA. Emerging evidence indicate that initiating events may occur at mucosal surfaces including oral cavity, lung and gut influenced by the local microbiome. Therefore, identifying the microbiome characteristics in prospective cohorts of at-risk individuals enables risk prediction or prevention of RA. Objectives: Here, we undertook this study to clarify the intestinal microbiota changes in individuals at high risk for RA. Meanwhile, we performed fecal transplantation study to investigate whereby the intestinal dysbiosis in the pre-RA population contributes to RA initiation and development, and provide a new prevention strategy for the treatment of this disease. Methods: 42 high-risk for RA individuals (Pre-RA), who were defined as having a positive serum antibody for anti-cyclic citrullinated peptide (CCP), 31 RA patients and 38 healthy individuals (HC) were recruited in this study. The V3-V4 region of 16S ribosomal RNA of fecal samples from these individuals were sequenced. We evaluated the gut permeability and the gut barrier dysfuction using HE staining and RT-PCR in mice receiving fecal transplantation (FMT). Flow cytometry was applied to measure the proportions of T cell subsets in immune organs. The disease severity of collagen-induced arthritis (CIA) was also evaluated after the mice receiving FMT. Results: Alpha diversity analysis showed a comparable community richness and a lower community diversity of the intestinal microbiota in Pre-RA compared to HC (Fig 1A). At the family level, the abundance of Bacteroidaceae gradually decreased from HC to Pre-RA individuals and to RA patients (Fig 1B). On the contrary, the enriched abundances of Streptococcaceae, Lactobacillus, Lactococcus, Weissella and unclassified_o_Lactobacillales were observed in RA patients (Fig 1B). There was different intestinal microbiota construction between groups based on principal coordinate analysis (PCoA). The intestinal microbiota communities dynamically shifted from HC to Pre-RA and to RA patients (Fig.1C). Fecal transplantation study showed that gut microbiota from Pre-RA group (P) significantly increased the fluorescence intensity (Fig 2A), accompanied with a significantly decreased ZO-1 gene expression (Fig 2B), and injured epithelial microvilli of the small intestine (Fig 2C). Moreover, the percentages of Th17 cells in the mesenteric lymph nodes (mLN) and peyer patches (PP) were also significantly increased in P and R groups (Fig 2D, E). Importantly, in CIA models, the joints redness and swelling in the mice receiving Pre-RA faeces occurred earlier and were more severe compared to HC-transplanted mice (Fig 2F, G and H). Figure 1. Figure 2. Conclusion: The intestinal microbiota changed gradually during disease progression of human rheumatoid arthritis. The gut microbiota from Pre-RA individuals can trigger the gut barrier dysfunction and intestinal mucosal immunity imbalance, which may further contribute to the arthritis initiation and development. References: [1]Brusca, S. B., Abramson, S. B. & Scher, J. U. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol 26 , 101-107, doi:10.1097/bor.0000000000000008 (2014). [2]Rogers, G. B. Germs and joints: the contribution of the human microbiome to rheumatoid arthritis. Nat. Med. 21 , 839-841, doi:10.1038/nm.3916 (2015). [3]Holers, V. M. et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nature reviews. Rheumatology , doi:10.1038/s41584-018-0070-0 (2018). Acknowledgments: The work of the authors is supported by National Natural Science Foundation of China (Grant Number: 81770101, 81403041) and Outstanding interdisciplinary project of West China Hospital, Sichuan University (Grant Number: ZYJC18024). Disclosure of Interests: None declared
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