Hyaluronan 2016–2021

More than 1100 published papers during 2016–2021 have "hyaluronan” in the title. This Encyclopedia of Cell Biology update focuses on 25 of these publications that we considered having important new directions for research on this fascinating Zen macromolecule that has a simple disaccharide structure and a very complex biology. There are likely several more publications during this time that fit this criteria. As hyaluronan has its own International Society (ISHAS) that meets biannually, the on-line booklets of meetings during this time provide insight into the wide range of ongoing hyaluronan research. © 2023 Elsevier Inc. All rights reserved.

Targeting tumor-associated macrophages for cancer immunotherapy.

Tumor-associated macrophages (TAMs) are one of the most abundant immune components in the tumor microenvironment and play a plethora of roles in regulating tumorigenesis. Therefore, the therapeutic targeting of TAMs has emerged as a new paradigm for immunotherapy of cancer. Herein, the review summarizes the origin, polarization, and function of TAMs in the progression of malignant diseases. The understanding of such knowledge leads to several distinct therapeutic strategies to manipulate TAMs to battle cancer, which include those to reduce TAM abundance, such as depleting TAMs or inhibiting their recruitment and differentiation, and those to harness or boost the anti-tumor activities of TAMs such as blocking phagocytosis checkpoints, inducing antibody-dependent cellular phagocytosis, and reprogramming TAM polarization. In addition, modulation of TAMs may reshape the tumor microenvironment and therefore synergize with other cancer therapeutics. Therefore, the rational combination of TAM-targeting therapeutics with conventional therapies including radiotherapy, chemotherapy, and other immunotherapies is also reviewed. Overall, targeting TAMs presents itself as a promising strategy to add to the growing repertoire of treatment approaches in the fight against cancer, and it is hopeful that these approaches currently being pioneered will serve to vastly improve patient outcomes and quality of life.

Excessive IL-10 and IL-18 trigger hemophagocytic lymphohistiocytosis-like hyperinflammation and enhanced myelopoiesis.

BACKGROUND: Hyperinflammation is a life-threatening condition associated with various clinical disorders characterized by excessive immune activation and tissue damage. Multiple cytokines promote the development of hyperinflammation; however, the contribution of IL-10 remains unclear despite emerging speculations for a pathological role. Clinical observations from hemophagocytic lymphohistiocytosis (HLH), a prototypical hyperinflammatory disease, suggest that IL-18 and IL-10 may collectively promote the onset of a hyperinflammatory state. OBJECTIVE: We aimed to investigate the collaborative roles of IL-10 and IL-18 in hyperinflammation. METHODS: A comprehensive plasma cytokine profile for 87 secondary HLH patients was first depicted and analyzed. We then investigated the systemic and cellular effects of coelevated IL-10 and IL-18 in a transgenic mouse model and cultured macrophages. Single-cell RNA sequencing was performed on the monocytes/macrophages isolated from secondary HLH patients to explore the clinical relevance of IL-10/IL-18-mediated cellular signatures. The therapeutic efficacy of IL-10 blockade was tested in HLH mouse models. RESULTS: Excessive circulating IL-10 and IL-18 triggered a lethal hyperinflammatory disease recapitulating HLH-like phenotypes in mice, driving peripheral lymphopenia and a striking shift toward enhanced myelopoiesis in the bone marrow. IL-10 and IL-18 polarized cultured macrophages to a distinct proinflammatory state with pronounced expression of myeloid cell-recruiting chemokines. Transcriptional characterization suggested the IL-10/IL-18-mediated cellular features were clinically relevant with HLH, showing enhanced granzyme expression and proteasome activation in macrophages. IL-10 blockade protected against the lethal disease in HLH mouse models. CONCLUSION: Coelevated IL-10 and IL-18 are sufficient to drive HLH-like hyperinflammatory syndrome, and blocking IL-10 is protective in HLH models.

Fu-Zheng-Xuan-Fei formula promotes macrophage polarization and Th17/Treg cell homeostasis against the influenza B virus (Victoria strain) infection.

ETHNOPHARMACOLOGICAL RELEVANCE: Fu-Zheng-Xuan-Fei formula (FF) is a prescription that has been clinically used through the basic theory of traditional Chinese medicine (TCM) for treating viral pneumonia. Although FF possesses a prominent clinical therapeutic effect, seldom pharmacological studies have been reported on its anti-influenza B virus (IBV) activity. AIM OF THE STUDY: Influenza is an acute infectious respiratory disease caused by the influenza virus, which has high annual morbidity and mortality worldwide. With a global decline in the COVID-19 control, the infection rate of influenza virus is gradually increasing. Therefore, it is of great importance to develop novel drugs for the effective treatment of influenza virus. Apart from conventional antiviral drugs, TCM has been widely used in the clinical treatment of influenza in China. Therefore, studying the antiviral mechanism of TCM can facilitate the scientific development of TCM. MATERIALS AND METHODS: Madin-Darby canine kidney cells (MDCK) and BALB/c mice were infected with IBV, and FF was added to evaluate the anti-IBV effects of FF both in vitro and in vivo by Western blotting, immunofluorescence, flow cytometry, and pathological assessment. RESULTS: It was found that FF exhibited anti-viral activity against IBV infection both in vivo and in vitro, while inducing macrophage activation and promoting M1 macrophage polarization. In addition, FF effectively regulated the signal transducer and activator of transcription (STAT) signaling pathway-mediated Th17/Treg balance to improve the lung tissue damage caused by IBV infection-induced inflammation. The findings provided the scientific basis for the antiviral mechanism of FF against IBV infection. CONCLUSIONS: This study shows that FF is a potentially effective antiviral drug against IBV infection.

Antiviral effects of Atractyloside A on the influenza B virus (Victoria strain) infection.

Influenza viruses pose a serious threat to human health, infecting hundreds of millions of people worldwide each year, resulting in a significant increase in global morbidity and mortality. Influenza activity has declined at the onset of the COVID-19 pandemic, but the genetic diversity of B/Victoria lineage viruses has increased significantly during this period. Therefore, the prevention and treatment of the influenza B Victoria strain virus should continue to attract research attention. In this study, we found that Atractyloside A (AA), one of the effective components in Atractylodes lancea (Thunb.) DC shows potential antiviral properties. This study shows that AA not only possesses anti-influenza B virus infection effects in vivo and in vitro but also can regulate macrophage polarization to the M2 type, which can effectively attenuate the damage caused by influenza B virus infection. Therefore, Atractyloside A may be an effective natural drug against B/Victoria influenza infection.

Kaempferol has potential anti-coronavirus disease 2019 (COVID-19) targets based on bioinformatics analyses and pharmacological effects on endotoxin-induced cytokine storm.

COVID-19 has infected 272 million patients and caused 5.33 million deaths around the world, and it remains the main global threat. Previous studies revealed that Chinese traditional medicine is an effective treatment for COVID-19 infection. This study aims to reveal the pharmacological effects of kaempferol, which is the active component of Radix Bupleuri and Tripterygii Radix, and potential mechanisms for the treatment of COVID-19. Here, we employed the bioinformatics methods to filter the anti-COVID-19 candidate genes of kaempferol, which mainly enriched in inflammation (TNF, JUN, etc.) and virus infection (AKT1, JNK, etc.). The Transcription levels of AKT1, JNK and JUN were significantly reduced by kaempferol treatment in the LPS-activated macrophages. In addition, kaempferol reduced the secretion of inflammatory factors by LPS-stimulated macrophages, inhibited MAPK/NF-κB signaling and regulated macrophage polarization to M2 type in vitro, and suppressed endotoxin-induced cytokine storm and improved survival in mice. Molecular docking analysis demonstrated that kaempferol was probable to bind the COVID-19 protein 5R84 and formatted hydrogen bond with the residues, the free binding energy of which was lower than the original ligand. In summary, our current work indicates that kaempferol has anti-COVID-19 potential through the reduction of COVID-19-induced body dysfunction and molecule-protein interaction, and bioinformatics results clarify that some of these key target genes might serve as potential molecular markers for detecting COVID-19.

Amelioration of Lung Fibrosis by Total Flavonoids of Astragalus via Inflammatory Modulation and Epithelium Regeneration.

Idiopathic Pulmonary Fibrosis (IPF) is identifiable by the excessive increase of mesenchyme paired with the loss of epithelium. Total flavonoids of Astragalus (TFA), the main biologically active ingredient of the traditional Chinese medicine, Astragalus membranaceus (Huangqi), shows outstanding effects on treating pulmonary disorders, including COVID-19-associated pulmonary dysfunctions. This study was designed to evaluate the efficacy of TFA on treating pulmonary fibrosis and the possible mechanisms behind these effects. A549 cells were treated with TGF-[Formula: see text]1 and TFA to observe the potential effects of TFA on regulating alveolar epithelial cell proliferation, TGF-[Formula: see text]1-induced EMT, and the underlying mechanisms in vitro. Then, mouse pulmonary fibrosis was induced with a single intra-tracheal injection of bleomycin, and TFA was administrated by i.p. injection. Lung fibrosis was evaluated through histological and molecular analyses, and the possible mechanisms were explored using immunological methods. The results demonstrated that TFA could promote cell proliferation but inhibit TGF-[Formula: see text]1-induced EMT on A549 cells. TFA attenuated BLM-induced pulmonary fibrosis in mice by modulating inflammatory infiltration and M2 macrophage polarization; it furthermore modulated EMT through regulating the TGF-[Formula: see text]1/Smad pathway. In addition, TFA augmented the expression of the Wnt7b protein, which plays an important role in alveolar epithelium reparation. In conclusion, TFA alleviated bleomycin-induced mouse lung fibrosis by preventing the fibrotic response and increasing epithelium regeneration.

Locked in a pro-inflammatory state.

Macrophages absorbing cells infected with viable SARS-CoV-2 particles fail to transition into an anti-inflammatory state, potentially contributing to a damaging immune reaction linked to severe forms of COVID-19.

Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells.

COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.

Depletion of γδ T Cells Leads to Reduced Angiogenesis and Increased Infiltration of Inflammatory M1-like Macrophages in Ischemic Muscle Tissue

γδ T cells, a small subset of T cells in blood, play a substantial role in influencing immunoregulatory and inflammatory processes. The functional impact of γδ T cells on angiogenesis in ischemic muscle tissue has never been reported and is the topic of the present work. Femoral artery ligation (FAL) was used to induce angiogenesis in the lower leg of γδ T cell depleted mice and wildtype and isotype antibody-treated control groups. Gastrocnemius muscle tissue was harvested 3 and 7 days after FAL and assessed using (immuno-)histological analyses. Hematoxylin and Eosin staining showed an increased area of tissue damage in γδ T cell depleted mice 7 days after FAL. Impaired angiogenesis was demonstrated by lower capillary to muscle fiber ratio and decreased number of proliferating endothelial cells (CD31+/BrdU+). γδ T cell depleted mice showed an increased number of total leukocytes (CD45+), neutrophils (MPO+) and neutrophil extracellular traps (NETs) (MPO+/CitH3+), without changes in the neutrophils to NETs ratio. Moreover, the depletion resulted in a higher macrophage count (DAPI/CD68+) caused by an increase in inflammatory M1-like macrophages (CD68+/MRC1−). Altogether, we show that depletion of γδ T cells leads to increased accumulation of leukocytes and M1-like macrophages, along with impaired angiogenesis.

Mesenchymal Stem Cells-derived Exosomes Ameliorate Lupus by Inducing M2 Macrophage Polarization and Regulatory T Cell Expansion in MRL/lpr Mice.

Previous studies have implicated that the transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) effectively alleviates systemic lupus erythematosus (SLE) primarily due to immunomodulatory effects. However, little is known about the role of hUC-MSC-derived exosomes in SLE. This study is carried out to investigate the modifying effects of hUC-MSC-exosomes on the differentiation and function of immune cells in SLE. hUC-MSC-derived exosomes were extracted from the cultural supernatant of hUC-MSCs by ultrahigh speed centrifugation. Quantitative real-time polymerase chain reaction, western blot, enzyme-linked immunosorbent assay, and flow cytometry were performed to estimate the effect of hUC-MSC-derived exosomes on macrophage and regulatory T cell (Treg) polarization. In vivo, hUC-MSC-exosomes were injected intravenously into 28-week-old MRL/lpr mice. We had found that exosomes derived from hUC-MSC restrained the proliferation and inflammation of macrophages in vitro. Besides, MSC-exosomes inhibited CD68+M1 and HLA-DR+M1 but promoted CD206+M2 and CD163+M2 in vitro. Moreover, MRL/lpr mice administrated by intravenous injection of MSC-exosomes had less infiltration of CD14+CD11c+M1 cells but more CD14+CD163+M2 cells as well as Tregs in spleens compared with those in MRL/lpr mice treated by PBS. Additionally, MSC-exosomes could alleviate nephritis, liver and lung injuries of MRL/lpr mice. The survival of lupus mice could be improved after MSC-exosome treatment. This study has suggested that MSC-derived exosomes exert anti-inflammatory and immunomodulatory effects in SLE. MSC-exosomes ameliorate nephritis and other key organ injuries by inducing M2 macrophages and Tregs polarization. As natural nanocarriers, MSC-exosomes may serve as a promising cell-free therapeutic strategy for SLE.Abbreviations: SLE: Systemic lupus erythematosus; hUC-MSCs: Human umbilical cord mesenchymal stem cells; MSCs: Mesenchymal stem cells; qRT-PCR: Quantitative real-time polymerase chain reaction; ELISA: Enzyme-linked immunosorbent assay; Tregs: Regulatory cells; TNF-α: Tumor necrosis factor alfa; IL: Interleukin; COVID-19: Coronavirus disease 2019; pTHP-1: PMA-induced THP-1 macrophages; TEM: Transmission electron microscopy; LPS: Lipopolysaccharide; EVs: Extracellular vesicles; TRAF1: Tumor necrosis factor receptor-associated factor 1; IRAK1: Interferon-α-interleukin-1 receptor-associated kinase 1; NF-κB: Nuclear factor-κB; BLyS: B lymphocyte stimulator; APRIL: A proliferation-inducing ligand.

The Gene Signature of Activated M-CSF-Primed Human Monocyte-Derived Macrophages Is IL-10-Dependent.

During inflammatory responses, monocytes are recruited into inflamed tissues, where they become monocyte-derived macrophages and acquire pro-inflammatory and tissue-damaging effects in response to the surrounding environment. In fact, monocyte-derived macrophage subsets are major pathogenic cells in inflammatory pathologies. Strikingly, the transcriptome of pathogenic monocyte-derived macrophage subsets resembles the gene profile of macrophage colony-stimulating factor (M-CSF)-primed monocyte-derived human macrophages (M-MØ). As M-MØ display a characteristic cytokine profile after activation (IL10high TNFlow IL23low IL6low), we sought to determine the transcriptional signature of M-MØ upon exposure to pathogenic stimuli. Activation of M-MØ led to the acquisition of a distinctive transcriptional profile characterized by the induction of a group of genes (Gene set 1) highly expressed by pathogenic monocyte-derived macrophages in COVID-19 and whose presence in tumor-associated macrophages (TAM) correlates with the expression of macrophage-specific markers (CD163, SPI1) and IL10. Indeed, Gene set 1 expression was primarily dependent on ERK/p38 and STAT3 activation, and transcriptional analysis and neutralization experiments revealed that IL-10 is not only required for the expression of a subset of genes within Gene set 1 but also significantly contributes to the idiosyncratic gene signature of activated M-MØ. Our results indicate that activation of M-CSF-dependent monocyte-derived macrophages induces a distinctive gene expression profile, which is partially dependent on IL-10, and identifies a gene set potentially helpful for macrophage-centered therapeutic strategies.

Xuanfei Baidu Decoction protects against macrophages induced inflammation and pulmonary fibrosis via inhibiting IL-6/STAT3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xuanfei Baidu Decoction (XFBD), one of the "three medicines and three prescriptions" for the clinically effective treatment of COVID-19 in China, plays an important role in the treatment of mild and/or common patients with dampness-toxin obstructing lung syndrome. AIM OF THE STUDY: The present work aims to elucidate the protective effects and the possible mechanism of XFBD against the acute inflammation and pulmonary fibrosis. METHODS: We use TGF-ß1 induced fibroblast activation model and LPS/IL-4 induced macrophage inflammation model as in vitro cell models. The mice model of lung fibrosis was induced by BLM via endotracheal drip, and then XFBD (4.6 g/kg, 9.2 g/kg) were administered orally respectively. The efficacy and molecular mechanisms in the presence or absence of XFBD were investigated. RESULTS: The results proved that XFBD can effectively inhibit fibroblast collagen deposition, down-regulate the level of α-SMA and inhibit the migration of fibroblasts. IL-4 induced macrophage polarization was also inhibited and the secretions of the inflammatory factors including IL6, iNOS were down-regulated. In vivo experiments, the results proved that XFBD improved the weight loss and survival rate of the mice. The XFBD high-dose administration group had a significant effect in inhibiting collagen deposition and the expression of α-SMA in the lungs of mice. XFBD can reduce bleomycin-induced pulmonary fibrosis by inhibiting IL-6/STAT3 activation and related macrophage infiltration. CONCLUSIONS: Xuanfei Baidu Decoction protects against macrophages induced inflammation and pulmonary fibrosis via inhibiting IL-6/STAT3 signaling pathway.

COVID-19: Mechanistic Model of the African Paradox Supports the Central Role of the NF-κB Pathway.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has expanded into a global pandemic, with more than 220 million affected persons and almost 4.6 million deaths by 8 September 2021. In particular, Europe and the Americas have been heavily affected by high infection and death rates. In contrast, much lower infection rates and mortality have been reported generally in Africa, particularly in the sub-Saharan region (with the exception of the Southern Africa region). There are different hypotheses for this African paradox, including less testing, the young age of the population, genetic disposition, and behavioral and epidemiological factors. In the present review, we address different immunological factors and their correlation with genetic factors, pre-existing immune status, and differences in cytokine induction patterns. We also focus on epidemiological factors, such as specific medication coverage, helminth distribution, and malaria endemics in the sub-Saharan region. An analysis combining different factors is presented that highlights the central role of the NF-κB signaling pathway in the African paradox. Importantly, insights into the interplay of different factors with the underlying immune pathological mechanisms for COVID-19 can provide a better understanding of the disease and the development of new targets for more efficient treatment strategies.

Is SARS-CoV-2 Spike glycoprotein impairing macrophage function via α7-nicotinic acetylcholine receptors?

The innate immune cells play an important role in handling early infections, and can eliminate them completely up to a certain threshold. Beyond that threshold they take up their role in "The Resolution of Inflammation". The recognition of the SARS-CoV-2 antigen triggers an eicosanoid storm and initiates a robust inflammatory response. This establishes a positive feedback loop which develops into a sustained cytokine storm which interferes with the activation of adaptive immune cells. The mechanism of this interaction, and hence the pathogenesis of the virus with the immune system, is yet to be determined. In silico studies predict a direct SARS-CoV-2 spike glycoprotein interaction with nicotinic acetylcholine receptors, which could impair macrophage function and initiate the cascade of events in severe infections. We here, add to the hypothesis that immune dysregulation can be caused by the interaction of the SARS-CoV-2 spike glycoprotein via a cryptic epitope with the α7-nAChR in Type-1 macrophages, discuss its implications for the treatment of COVID-19 patients, and present better prospects for the design and dissemination of more effective vaccines and their importance.

Manganese nanodepot augments host immune response against coronavirus.

Interferon (IFN) responses are central to host defense against coronavirus and other virus infections. Manganese (Mn) is capable of inducing IFN production, but its applications are limited by nonspecific distributions and neurotoxicity. Here, we exploit chemical engineering strategy to fabricate a nanodepot of manganese (nanoMn) based on Mn2+. Compared with free Mn2+, nanoMn enhances cellular uptake and persistent release of Mn2+ in a pH-sensitive manner, thus strengthening IFN response and eliciting broad-spectrum antiviral effects in vitro and in vivo. Preferentially phagocytosed by macrophages, nanoMn promotes M1 macrophage polarization and recruits monocytes into inflammatory foci, eventually augmenting antiviral immunity and ameliorating coronavirus-induced tissue damage. Besides, nanoMn can also potentiate the development of virus-specific memory T cells and host adaptive immunity through facilitating antigen presentation, suggesting its potential as a vaccine adjuvant. Pharmacokinetic and safety evaluations uncover that nanoMn treatment hardly induces neuroinflammation through limiting neuronal accumulation of manganese. Therefore, nanoMn offers a simple, safe, and robust nanoparticle-based strategy against coronavirus. Electronic Supplementary Material: Supplementary material (RNA-seq data analysis, IFN and ISGs examination, in vitro viral infection, flow cytometry, ICP-MS, DHE staining, and detection of inflammatory factors) is available in the online version of this article at 10.1007/s12274-020-3243-5.