Immune modulation by complement receptor 3-dependent human monocyte TGF-β1-transporting vesicles

Halder, Luke D.; Jo, Emeraldo A.H.; Hasan, M.Z.; Ferreira‐Gomes, Marta; Krüger, Thomas; Westermann, Martin; Palme, Diana I; Rambach, Günter; Beyersdorf, Niklas; Speth, Cornelia; Jacobsen, Ilse D.; Kniemeyer, Olaf; Jungnickel, Berit; Zipfel, Peter F.; Skerka, Christine

doi:10.1038/s41467-020-16241-5

Cited by 44 publications

(29 citation statements)

References 72 publications

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“…Multiple immune cells, aside from neutrophils, harbor receptors capable of recognizing exposed ß(1,3)-glucan and chitin and initiating an immune response. These cell types include important immune modulators such as monocytes, macrophages, dendritic cells and host epithelial cells [ 7 , 14 , 34 , 38 , 55 ]. Our data have already shown increased immune activation of murine macrophages in vitro in response to exposure to unmasked STE11 ΔN467 cells ( Fig 3D ), and it is likely that tissue resident and infiltrating macrophages play a similar role in recognizing and initiating an immune response against unmasked fungal cells within the kidney.…”

Section: Discussionmentioning

confidence: 99%

Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner

et al. 2021

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Masking the immunogenic cell wall epitope ß(1,3)-glucan under an outer layer of mannosylated glycoproteins is an important virulence factor deployed by Candida albicans during infection. Consequently, increased ß(1,3)-glucan exposure (unmasking) reveals C. albicans to the host’s immune system and attenuates its virulence. We have previously shown that activation of the Cek1 MAPK pathway via expression of a hyperactive allele of an upstream kinase (STE11ΔN467) induces unmasking. It also increased survival of mice in a murine disseminated candidiasis model and attenuated kidney fungal burden by ≥33 fold. In this communication, we utilized cyclophosphamide-induced immunosuppression to test if the clearance of the unmasked STE11ΔN467 mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the STE11ΔN467 allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced STE11ΔN467-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked STE11ΔN467 cells. In an effort to understand the mechanism by which Ste11ΔN467 causes unmasking, transcriptomics were used to reveal that several components in the Cek1 MAPK pathway were upregulated, including the transcription factor CPH1 and the cell wall sensor DFI1. In this report we show that a cph1ΔΔ mutation restored ß(1,3)-glucan exposure to wild-type levels in the STE11ΔN467 strain, confirming that Cph1 is the transcription factor mediating Ste11ΔN467-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by STE11ΔN467 is dependent on the upstream cell wall sensor DFI1. However, while deletion of DFI1 significantly reduced Ste11ΔN467-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11ΔN467, Dfi1 activates a parallel signaling pathway that is involved in Ste11ΔN467-induced unmasking.

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Section: Discussionmentioning

confidence: 99%

Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner

et al. 2021

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“…small β-glucan particles with a backbone length below seven glucose units cannot bind to dectin-1, and soluble β-glucans cannot initiate clustering of dectin-1 in immunological synapses, and consequently cannot activate this receptor [ 39 ]. It is noteworthy, however, that soluble β-glucans are able to bind to the complement receptor 3 and support humoral immune responses [ 40 , 41 ]. When taken current viewpoints together, both soluble and insoluble β-glucan fractions are capable of supporting immune responses, yet we argue that the β-glucan activity towards the production of chemo-attractants and potentially towards a cellular immune response is expected to be linked to insoluble β-glucans.…”

Section: Discussionmentioning

confidence: 99%

Curdlan, zymosan and a yeast-derived β-glucan reshape tumor-associated macrophages into producers of inflammatory chemo-attractants

Graaff

Berrevoets

Rösch

et al. 2020

Cancer Immunol Immunother

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Anti-cancer T-cell responses are often halted due to the immune-suppressive micro-environment, in part related to tumorassociated macrophages. In the current study, we assessed indigestible β-glucans (oatβG, curdlan, grifolan, schizophyllan, lentinan, yeast whole glucan particles (yWGP), zymosan and two additional yeast-derived β-glucans a and b) for their physicochemical properties as well as their effects on the plasticity of human monocyte-derived macrophages that were polarized with IL-4 to immune-suppressive macrophages. Beta-glucans were LPS/LTA free, and tested for solubility, molecular masses, protein and monosaccharide contents. Curdlan, yeast-b and zymosan re-polarized M(IL-4) macrophages towards an M1-like phenotype, in particular showing enhanced gene expression of CCR7, ICAM1 and CD80, and secretion of TNF-α and IL-6. Notably, differential gene expression, pathway analysis as well as protein expressions demonstrated that M(IL-4) macrophages treated with curdlan, yeast-b or zymosan demonstrated enhanced production of chemo-attractants, such as CCL3, CCL4, and CXCL8, which contribute to recruitment of monocytes and neutrophils. The secretion of chemo-attractants was confirmed when using patient-derived melanoma-infiltrating immune cells. Taken together, the bacterial-derived curdlan as well as the yeast-derived β-glucans yeast-b and zymosan have the unique ability to preferentially skew macrophages towards a chemoattractant-producing phenotype that may aid in anti-cancer immune responses. Keywords Beta-glucans • Macrophages • Chemokines • Chemo-attractants Abbreviations CR3 Complement receptor 3 Conv CD4 T cell Conventional cluster of differentiation 4 T cell LacCer Lactosylceramide LCF Lymphocyte chemoattractant factor LTA Lipoteichoic acid Tig-2 Tazarotene-induced gene 2 protein Treg Regulatory T cell yWGP Yeast whole glucan particle

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“…Phagocytosis of apoptotic bodies enhances TGF-β production, which is a well-known pro-fibrogenic cytokine and has pro-apoptotic function in the liver. Recently it has been identified that apoptotic bodies induce the release of TGF-β transporting monocytic extracellular vesicles [ 123 ]. Engulfment of apoptotic bodies by HSCs induces NADPH oxidase and is associated with liver fibrosis in vivo [ 124 ].…”

Section: Role Of Apoptotic Bodies In Hepatic Fibrosismentioning

confidence: 99%

Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?

Khanam

Saleeb

Kottilil

2021

Cells

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Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, resulting in inflammation. Excessive inflammation drives hepatic stellate cell (HSC) activation, which then encounters various morphological and functional changes before transforming into proliferative and extracellular matrix (ECM)-producing myofibroblasts. Finally, enormous ECM accumulation interferes with hepatic function and leads to liver failure. To overcome this condition, several therapeutic approaches have been developed to inhibit inflammatory responses, HSC proliferation and activation. Preclinical studies also suggest several targets for the development of anti-fibrotic therapies; however, very few advanced to clinical trials. The pathophysiology of hepatic fibrosis is extremely complex and requires comprehensive understanding to identify effective therapeutic targets; therefore, in this review, we focus on the various cellular and molecular mechanisms associated with the pathophysiology of hepatic fibrosis and discuss potential strategies to control or reverse the fibrosis.

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Immune modulation by complement receptor 3-dependent human monocyte TGF-β1-transporting vesicles

Cited by 44 publications

References 72 publications

Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner

Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner

Curdlan, zymosan and a yeast-derived β-glucan reshape tumor-associated macrophages into producers of inflammatory chemo-attractants

Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?

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