Macrophage-biomimetic porous Se@SiO2 nanocomposites for dual modal immunotherapy against inflammatory osteolysis

Abstract Background Inflammatory osteolysis, a major complication of total joint replacement surgery, can cause prosthesis failure and necessitate revision surgery. Macrophages are key effector immune cells in inflammatory responses, but excessive M1-polarization of dysfunctional macrophages leads to the secretion of proinflammatory cytokines and severe loss of bone tissue. Here, we report the development of macrophage-biomimetic porous SiO2-coated ultrasmall Se particles (porous Se@SiO2 nanospheres) to manage inflammatory osteolysis. Results Macrophage membrane-coated porous Se@SiO2 nanospheres(M-Se@SiO2) attenuated lipopolysaccharide (LPS)-induced inflammatory osteolysis via a dual-immunomodulatory effect. As macrophage membrane decoys, these nanoparticles reduced endotoxin levels and neutralized proinflammatory cytokines. Moreover, the release of Se could induce macrophage polarization toward the anti-inflammatory M2-phenotype. These effects were mediated via the inhibition of p65, p38, and extracellular signal-regulated kinase (ERK) signaling. Additionally, the immune environment created by M-Se@SiO2 reduced the inhibition of osteogenic differentiation caused by proinflammation cytokines, as confirmed through in vitro and in vivo experiments. Conclusion Our findings suggest that M-Se@SiO2 have an immunomodulatory role in LPS-induced inflammation and bone remodeling, which demonstrates that M-Se@SiO2 are a promising engineered nanoplatform for the treatment of osteolysis occurring after arthroplasty. Graphical Abstract

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Macrophage-Biomimetic Porous Se@SiO2 Nanocomposites For “Dual Model” Immunotherapy Against Inflammatory Osteolysis

10.21203/rs.3.rs-885656/v1 ◽

2021 ◽

Author(s):

Cheng Ding ◽

Chuang Yang ◽

Tao Cheng ◽

Xingyan Wang ◽

Qiaojie Wang ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Total Joint Replacement ◽

Major Complication ◽

Dual Model ◽

Joint Replacement Surgery ◽

Pro Inflammatory Cytokines ◽

Macrophage Membrane

Abstract Background：Inflammatory osteolysis is a major complication of total joint replacement surgery that can cause prosthesis failure and necessitate revision surgery. Macrophages are key effector immune cells in inflammatory responses, but excessive M1-polarization of dysfunctional macrophages leads to the secretion of pro-inflammatory cytokines and severe loss of bone tissue. Here, we report the development of macrophage-biomimetic porous SiO2-coated ultrasmall Se particles (Porous Se@SiO2 nanospheres) for the management of inflammatory osteolysis. Results: Macrophage-membrane-coated porous Se@SiO2 nanospheres(M-Se@SiO2) can attenuate lipopolysaccharide (LPS)-induced inflammatory osteolysis by a dual-immunomodulatory effect. As macrophage membrane decoys, these nanoparticles reduce toxin levels and neutralize pro-inflammatory cytokines. Moreover, the release of Se can induce the polarization of macrophages toward the anti-inflammatory M2-phenotype. These effects are mediated via the inhibition of p65, p38, and extracellular signal-regulated kinase(ERK) signaling. Additionally, the immune environment created by M-Se@SiO2 reduces the inhibition of osteogenic differentiation caused by pro-inflammation cytokines, confirmed through in vitro and in vivo experiments.Conclusion: Our findings suggest that M-Se@SiO2 has an immunomodulatory role in LPS-induced inflammation and bone remodeling, which demonstrates that M-Se@SiO2 is a promising engineered nano-platform for the treatment of osteolysis arising after arthroplasty.

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Biocompatible N-acetyl-nanoconstruct alleviates lipopolysaccharide-induced acute lung injury in vivo

Scientific Reports ◽

10.1038/s41598-021-01624-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Seongchan Kim ◽

Shin Young Kim ◽

Seung Joon Rho ◽

Seung Hoon Kim ◽

So Hyang Song ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Intratracheal Instillation ◽

Sprague Dawley ◽

In Vivo Experiments ◽

Anti Inflammatory

AbstractOxidative stress plays important roles in inflammatory responses during acute lung injury (ALI). Recently, nanoconstruct (Nano)-based drug-delivery systems have shown promise in many models of inflammation. In this study, we evaluated the anti-inflammatory effects of N-acetylcysteine (NAC) loaded in a biocompatible Nano using a rat model of ALI. We synthesized a Nano with a good NAC-releasing capacity using porous silica Nano, which was used to produce Nano/NAC complexes. For in vivo experiments, Sprague–Dawley rats were intraperitoneally administered NAC or Nano/NAC 30 min after intratracheal instillation of lipopolysaccharide. After 6 h, bronchoalveolar lavage fluids and lung tissues were collected. The anti-oxidative effect of the Nano/NAC complex was confirmed by demonstrating reduced levels of reactive oxygen species after treatment with the Nano/NAC in vitro. In vivo experiments also showed that the Nano/NAC treatment may protect against LPS‐induced ALI thorough anti‐oxidative and anti‐inflammatory effects, which may be attributed to the inactivation of the NF‐κB and MAPK pathways. In addition, the effects of Nano/NAC treatment were shown to be superior to those of NAC alone. We suggest the therapeutic potential of Nano/NAC treatment as an anti‐inflammatory agent against ALI. Furthermore, our study can provide basic data for developing nanotechnology-based pharmacotherapeutics for ALI.

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Glycyrrhizin Protects Rats from Sepsis by Blocking HMGB1 Signaling

BioMed Research International ◽

10.1155/2017/9719647 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Feng Zhao ◽

Yong Fang ◽

Shuixiang Deng ◽

Xiantao Li ◽

Yun Zhou ◽

...

Keyword(s):

Cell Surface ◽

Proinflammatory Cytokines ◽

Inflammatory Mediator ◽

Inflammatory Responses ◽

Serum Levels ◽

Direct Stimulation ◽

Potential Therapeutic Target ◽

Surface Receptors

Background. HMGB1 acts as an important inflammatory mediator and is a potential therapeutic target for sepsis. Glycyrrhizin (GL), a natural triterpene glycoside derived from licorice, has been demonstrated to inhibit HMGB1 activity. The aim of this study is to explore how GL affects the HMGB1 signaling in sepsis. Methods. We used a CLP model of sepsis and in vitro LPS or HMGB1-treated NR8383 cells to examine the effects of GL on expression of HMGB1 and proinflammatory cytokines. Furthermore, we explored the effect of GL on interactions between HMGB1 and RAGE or TLR4 and the activations of NF-κB and MAPKs. Results. GL significantly decreased mortality and reduced serum levels of HMGB1 in vivo. GL also attenuated the release and expression of HMGB1 and proinflammatory cytokines. Direct stimulation by HMGB1 elevated the release of proinflammatory cytokines faster than LPS did and it was also inhibited by GL. Furthermore, GL blocked the interaction of HMGB1 with RAGE and TLR4 and suppressed the downstream MAPKs/NF-κB signaling pathway. Conclusion. GL may protect rats against sepsis by blocking the interaction of HMGB1 with cell surface receptors and HMGB1-mediated inflammatory responses.

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Plinabulin, a Distinct Microtubule-Targeting Chemotherapy, Promotes M1-Like Macrophage Polarization and Anti-tumor Immunity

Frontiers in Oncology ◽

10.3389/fonc.2021.644608 ◽

2021 ◽

Vol 11 ◽

Author(s):

Marina Natoli ◽

Petra Herzig ◽

Elham Pishali Bejestani ◽

Melanie Buchi ◽

Reto Ritschard ◽

...

Keyword(s):

Tumor Immunity ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Clinical Stage ◽

Dendritic Cell Maturation ◽

Tumor Growth Inhibition ◽

Healthy Human ◽

Jnk Pathway

Reprogramming tumor infiltrating myeloid cells to elicit pro-inflammatory responses is an exciting therapeutic maneouver to improve anti-tumor responses. We recently demonstrated that a distinct microtubule-targeting drug, plinabulin—a clinical-stage novel agent—modulates dendritic cell maturation and enhances anti-tumor immunity. Here, we investigated the effects of plinabulin on macrophage polarization in vitro and in vivo. Plinabulin monotherapy induced significant tumor growth inhibition in mice bearing subcutaneous MC38 colon cancer. Importantly, the regressing tumors were characterized by an increase in M1-like/M2-like tumor-associated macrophages (TAM) ratio. The efficacy of plinabulin remained unaltered in T cell-deficient Rag2−/− mice, suggesting an important role of macrophages in driving the drug's anti-tumor effect. Exposure of murine and healthy human macrophages to plinabulin induced polarization toward the M1 phenotype, including increased expression of co-stimulatory molecules CD80, CD86 and pro-inflammatory cytokines IL-1β, IL-6, and IL-12. M2-associated immunosuppressive cytokines IL-10 and IL-4 were reduced. This pro-inflammatory M1-like skewing of TAMs in response to plinabulin was dependent on the JNK pathway. Functionally, plinabulin-polarized human M1 macrophages directly killed HuT 78 tumor cells in vitro. Importantly, plinabulin induced a functional M1-like polarization of tumor infiltrating macrophages in murine tumors as well as in tumor samples from ovarian cancer patients, by preferentially triggering M1 proliferation. Our study uncovers a novel immunomodulatory effect of plinabulin in directly triggering M1 polarization and proliferation as well as promoting TAM anti-tumoral effector functions.

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Attenuation of Knee Osteoarthritis Progression in Mice through Polarization of M2 Macrophages by Intra-Articular Transplantation of Non-Cultured Human Adipose-Derived Regenerative Cells

Journal of Clinical Medicine ◽

10.3390/jcm10194309 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4309

Author(s):

Kohei Kamada ◽

Takehiko Matsushita ◽

Takahiro Yamashita ◽

Tomoyuki Matsumoto ◽

Hideki Iwaguro ◽

...

Keyword(s):

Macrophage Polarization ◽

Type Ii Collagen ◽

Control Group ◽

Knee Oa ◽

In Vivo Experiments ◽

Osteoarthritis Progression ◽

Regenerative Cells ◽

Related Proteins

Adipose-derived regenerative cells (ADRCs) are non-cultured heterogeneous or mixed populations of cells obtained from adipose tissue by collagenase digestion. The injection of ADRCs have been tried clinically for the treatment of osteoarthritis (OA). The purpose of this study was to evaluate the effect of intra-articular transplantation of human ADRCs on OA progression in mice and the effect of ADRCs on macrophage polarization. In in vivo experiments, BALB/c-nu mice with knee OA received intra-articular transplantation of either phosphate buffered-saline or human ADRCs. OA progression was evaluated histologically and significantly attenuated in the ADRC group at both four and eight weeks postoperatively. The expression of OA-related proteins in the cartilage and macrophage-associated markers in the synovium were examined by immunohistochemistry. The numbers of MMP-13-, ADAMTS-5-, IL-1β-, IL-6- and iNOS-positive cells significantly decreased, and type II collagen- and CD206-positive cells were more frequently detected in the ADRC group compared with that in the control group. In vitro co-culture experiments showed that ADRCs induced macrophage polarization toward M2. The results of this study suggest that the intra-articular transplantation of human ADRCs could attenuate OA progression possibly by reducing catabolic factors in chondrocytes and modulating macrophage polarization.

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Regulation of physiological and pathological Th1 and Th2 responses by lactoferrinThis paper is one of a selection of papers published in this Special Issue, entitled 7th International Conference on Lactoferrin: Structure, Function, and Applications, and has undergone the Journal's usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o06-058 ◽

2006 ◽

Vol 84 (3) ◽

pp. 303-311 ◽

Cited By ~ 54

Author(s):

Romy Fischer ◽

Hajer Debbabi ◽

Michel Dubarry ◽

Prosper Boyaka ◽

Daniel Tomé

Keyword(s):

Inflammatory Responses ◽

Peer Review Process ◽

Allergic Diseases ◽

Protective Effects ◽

In Vivo Experiments ◽

Cytokine Balance ◽

Th1 And Th2 Responses ◽

Th1 Polarization

In recent years, Lf has gained increasing interest as a result of its protective effects against a variety of diseases. While iron binding and interactions with mammalian receptors and microbial components are the best described mechanisms of action, recent studies have provided evidence that Lf properties may be related to immunoregulatory effects on Th1/Th2 cell activities. In vitro and in vivo experiments show that Lf is able to stimulate the differentiation of T cells from their immature precursors through the induction of the CD4 antigen. Studies performed under nonpathogenic conditions have shown distinct results with regard to the ability of Lf to support the proliferation and differentiation of Th cells into the Th1 or the Th2 phenotype. In addition, Lf plays different roles in diseases by affecting the Th1/Th2 cytokine balance in a manner dependent on the host’s immune status. Thus, Lf could cause a Th1 polarization in diseases in which the ability to control infection or tumor relies on a strong Th1 response. Lf may also reduce the Th1 component to limit excessive inflammatory responses. Finally, Lf may provide protection against Th1- or Th2-induced diseases, such as autoimmune or allergic diseases, through correction of the Th1/Th2 imbalance.

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Anti-Inflammatory Effects of Novel Glycyrrhiza Variety Wongam In Vivo and In Vitro

Applied Sciences ◽

10.3390/app112210822 ◽

2021 ◽

Vol 11 (22) ◽

pp. 10822

Author(s):

Yun-Mi Kang ◽

Jeonghoon Lee ◽

Wonnam Kim ◽

Jong-Sik Jin ◽

Jong-Hyun Lee ◽

...

Keyword(s):

Mast Cell ◽

Proinflammatory Cytokines ◽

Cell Activation ◽

Inflammatory Responses ◽

Immunoglobulin E ◽

Mast Cell Activation ◽

In Vivo Model ◽

Cell Surface Antigens

Licorice is the common name of Glycyrrhiza species, which is an important plant for edible and medicinal purposes; however, Glycyrrhiza resources have become limited because of desertification, depletion of natural resources, and environmental restrictions. For this reason, a novel Glycyrrhiza variety named Wongam, a hybrid of G. glabra and G. uralensis, was developed by the Korea Rural Development Administration. To elucidate the antiallergic inflammatory effects of Wongam, we investigated its effects using a compound-48/80-induced anaphylaxis in vivo model and PMA/A23187-stimulated HMC-1 cells and immunoglobulin E (IgE)/DNP-stimulated RBL-2H3 cells in in vitro models. Wongam treatment reduced mortality and serum IgE levels and downregulated proinflammatory cytokines and chemokines in a compound-48/80-induced anaphylaxis mouse model. Wongam decreased histamine release and the expression of proinflammatory cytokines in HMC-1 and RBL-2H3 cells. Wongam treatment downregulated the expression of chemokines, T helper 2 cytokines, and cell surface antigens in PMA/A23187-stimulated HMC-1 cells. We confirmed that these effects were associated with the inhibition of the MAPK and NF-κB signaling pathways by Wongam. The present study suggests that Wongam ameliorates mast-cell-mediated allergic inflammatory responses by reducing mast cell activation and may serve as an effective agent for the prevention and treatment of allergic inflammatory responses.

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SNHG15 is a negative regulator of inflammation by mediating TRAF2 ubiquitination in stroke-induced immunosuppression

Journal of Neuroinflammation ◽

10.1186/s12974-021-02372-z ◽

2022 ◽

Vol 19 (1) ◽

Author(s):

Huiling Sun ◽

Shuo Li ◽

Zhaohan Xu ◽

Chengfang Liu ◽

Pengyu Gong ◽

...

Keyword(s):

Mononuclear Cells ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Janus Kinase ◽

Negative Regulator ◽

Mitogen Activated Protein Kinase ◽

M2 Macrophage ◽

Peripheral Blood Mononuclear

Abstract Background Abnormal expression of long noncoding RNAs (lncRNAs) has been reported in the acute stage of acute ischemic stroke (AIS). This study aimed to explore differential lncRNA expression in the subpopulations of peripheral blood mononuclear cells (PBMCs) from AIS patients and further evaluate its underlying mechanisms in stroke-induced immunosuppression. Methods We reanalyzed lncRNA microarray data and investigated abnormally expressed lncRNAs in the subpopulations of PBMCs by magnetic cell sorting and real-time quantitative PCR. The potential mechanism of small nucleolar RNA host gene 15 (SNHG15) was explored through in vitro and in vivo approaches. Results The stroke-induced SNHG15 acted as a checkpoint to inhibit peripheral inflammatory responses. Functional studies showed that SNHG15 promoted M2 macrophage polarization. Mechanistically, SNHG15 expression was dysregulated through the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) signaling pathway. SNHG15, localized in the cytoplasm, interfered with K63-linked ubiquitination of tumor necrosis factor receptor-associated factor 2 and thereby repressed the activation of mitogen-activated protein kinase and nuclear factor kappa-B signaling pathways and prevented the production of proinflammatory cytokines. Administration of an adenovirus targeting SNHG15 improved stroke-induced immunosuppression in mice. Conclusions This study identified SNHG15 as a negative regulator of inflammation in stroke-induced immunosuppression, suggesting it as a novel biomarker and therapeutic target in stroke-associated infection. Trial registration ClinicalTrials.gov NCT04175691. Registered November 25, 2019, https://www.clinicaltrials.gov/ct2/show/NCT04175691.

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Apoptosis inhibitor of macrophage (AIM) contributes to IL-10-induced anti-inflammatory response through inhibition of inflammasome activation

Cell Death and Disease ◽

10.1038/s41419-020-03332-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tae-Hyun Kim ◽

Kyungwon Yang ◽

Minsuk Kim ◽

Hee-Sun Kim ◽

Jihee Lee Kang

Keyword(s):

Inflammatory Responses ◽

Macrophage Polarization ◽

Peritoneal Macrophages ◽

Inflammasome Activation ◽

M2 Macrophage ◽

Caspase 1 ◽

Apoptosis Inhibitor ◽

Apoptosis Inhibitor Of Macrophage

AbstractApoptosis inhibitor of macrophage (AIM) modulates the signaling in inflammatory responses, including infection, cancer, or other immune diseases. Recent studies suggest that like interleukin-10 (IL-10), AIM is involved in alternatively activated (M2) macrophage polarization. We aimed to understand whether and how AIM is involved in IL-10-induced inhibition of inflammasome activation and resolution of inflammation. First, we demonstrated that IL-10 induced increases in mRNA and protein expression of AIM in murine bone marrow-derived macrophages (BMDM). In addition, genetic and pharmacologic inhibition of STAT3 (signal transducer and activator of transcription 3) reduced IL-10-induced AIM expression. We also found that IL-10-induced STAT3 activity enhanced the AIM promoter activity by directly binding the promoter of the AIM gene. Additionally, reduction of LPS/adenosine triphosphate (ATP)-induced IL-1β production and caspase-1 activation by IL-10 was reversed in BMDM from AIM−/− mice. Treatment of BMDM from both wild type (WT) and IL-10−/− mice with recombinant AIM showed the inhibitory effects on IL-1β and IL-18 production and caspase-1 activation. Endogenous and exogenous AIM inhibited apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) speck formation. In LPS-induced acute peritonitis, inhibition of IL-1β and IL-18 production in peritoneal lavage fluid (PLF) and serum, reduction of caspase-1 activation in peritoneal macrophages, and reduction of numbers of neutrophils and peritoneal macrophages in PLF by administration of IL-10 were not evident in AIM−/− mice. Our in vitro and in vivo data reveal a novel role of AIM in the inhibition of inflammasome-mediated caspase-1 activation and IL-1β and IL-18 production.

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Macrophages Modulate Hepatic Injury Involving NLRP3 Inflammasome: The Example of Efavirenz

Biomedicines ◽

10.3390/biomedicines10010109 ◽

2022 ◽

Vol 10 (1) ◽

pp. 109

Author(s):

Fernando Alegre ◽

Alberto Martí-Rodrigo ◽

Miriam Polo ◽

Dolores Ortiz-Masiá ◽

Celia Bañuls ◽

...

Keyword(s):

Liver Injury ◽

Liver Cell ◽

Nlrp3 Inflammasome ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Cell Types ◽

Drug Induced ◽

Anti Inflammatory

Drug-induced liver injury (DILI) constitutes a clinical challenge due to the incomplete characterization of the mechanisms involved and potential risk factors. Efavirenz, an anti-HIV drug, induces deleterious actions in hepatocytes that could underlie induction of the NLRP3 inflammasome, an important regulator of inflammatory responses during liver injury. We assessed the potential of efavirenz to modulate the inflammatory and fibrogenic responses of major liver cell types involved in DILI. The effects of efavirenz were evaluated both in vitro and in vivo. Efavirenz triggered inflammation in hepatocytes, in a process that involved NF-κB and the NLRP3 inflammasome, and activated hepatic stellate cells (HSCs), thereby enhancing expression of inflammatory and fibrogenic markers. The NLRP3 inflammasome was not altered in efavirenz-treated macrophages, but these cells polarized towards the anti-inflammatory M2 phenotype and displayed upregulated anti-inflammatory mediators. Conversely, no evidence of damage was observed in efavirenz-treated animals, except when macrophages were depleted, which resulted in the in vivo manifestation of the deleterious effects detected in hepatocytes and HSCs. Efavirenz elicits a cell-specific activation of the NLRP3 inflammasome in hepatocytes and HSCs, but macrophages appear to counteract efavirenz-induced liver injury. Our results highlight the dynamic nature of the interaction among liver cell populations and emphasize the potential of targeting macrophage polarization as a strategy to treat NLRP3 inflammasome-induced liver injury.

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