Human Gut Commensal Membrane Vesicles Modulate Inflammation by Generating M2-like Macrophages and Myeloid-Derived Suppressor Cells

Abstract

Immunomodulatory commensal bacteria modify host immunity through delivery of regulatory microbial-derived products to host cells. Extracellular membrane vesicles (MVs) secreted from symbiont commensals represent one such transport mechanism. How MVs exert their anti-inflammatory effects or whether their tolerance-inducing potential can be used for therapeutic purposes remains poorly defined. In this study, we show that MVs isolated from the human lactic acid commensal bacteria Pediococcus pentosaceus suppressed Ag-specific humoral and cellular responses. MV treatment of bone marrow-derived macrophages and bone marrow progenitors promoted M2-like macrophage polarization and myeloid-derived suppressor cell differentiation, respectively, most likely in a TLR2-dependent manner. Consistent with their immunomodulatory activity, MV-differentiated cells upregulated expression of IL-10, arginase-1, and PD-L1 and suppressed the proliferation of activated T cells. MVs' antiinflammatory effects were further tested in acute inflammation models in mice. In carbon tetrachloride-induced fibrosis and zymosan-induced peritonitis models, MVs ameliorated inflammation. In the dextran sodium sulfate-induced acute colitis model, systemic treatment with MVs prevented colon shortening and loss of crypt architecture. In an excisional wound healing model, i.p. MV administration accelerated wound closure through recruitment of PD-L1-expressing myeloid cells to the wound site. Collectively, these results indicate that P. pentosaceus-derived MVs hold promise as therapeutic agents in management/treatment of inflammatory conditions.

The role of extracellular vesicles in the physiological and pathological regulation of the blood–brain barrier

“…HIV infection also increased the transfer of amyloid‐beta from BECs to astrocytes and pericytes through endothelial EVs, a process that was suggested to be involved in HIV‐associated neurocognitive disorder 61 . It is worth noting that, similar to host cell‐derived EVs, microbial EVs derived from pathogenic and nonpathogenic bacteria have been recently introduced as major players in the modulation of immune responses 62,63 . The similarities between the microbial EVs and their eukaryotic counterparts in the mechanisms of internalization into recipient cells prompts the hypothesis that microbial EVs could be taken up by BECs or breach the BBB and, therefore, contribute to immune regulation in the brain.…”

Effects of gut microbiota–derived extracellular vesicles on obesity and diabetes and their potential modulation through diet

“…It should be noted that gut microbiota EVs could not only exert immunomodulatory functions through their interaction with gut barrier cells, but they could also communicate with intestinal immune system cells, thus influencing host immunity. In this regard, Bulut et al [ 4 ] determined that EVs derived from the commensal bacterium Pediococcus pentosaceus triggered immuno-suppressive responses both in vitro and in vivo. Using several mouse models of acute inflammation, the authors showed that P. pentosaceus EVs promoted immune tolerance and inhibited inflammation through the direct interaction with bone marrow-derived macrophages and bone marrow progenitors by a TLR-2-dependent mechanism, which stimulates the generation of inflammation regulatory cells (M2-like macrophage and myeloid-derived suppressor-like cells) [ 4 ].…”

“…In this regard, Bulut et al [ 4 ] determined that EVs derived from the commensal bacterium Pediococcus pentosaceus triggered immuno-suppressive responses both in vitro and in vivo. Using several mouse models of acute inflammation, the authors showed that P. pentosaceus EVs promoted immune tolerance and inhibited inflammation through the direct interaction with bone marrow-derived macrophages and bone marrow progenitors by a TLR-2-dependent mechanism, which stimulates the generation of inflammation regulatory cells (M2-like macrophage and myeloid-derived suppressor-like cells) [ 4 ]. The protective effect of gut microbiota EVs against inflammatory disorders was also corroborated by Shen et al [ 113 ], who demonstrated that Bacteroides fragilis EVs prevented colitis development in mice by inducing immune tolerance through activation of dendritic cells [ 113 ].…”

Bacterial Extracellular Vesicles and the Gut‐Microbiota Brain Axis: Emerging Roles in Communication and Potential as Therapeutics

“…Probiotic BEVs can prevent inflammation in models of colitis, liver fibrosis, and peritonitis, and accelerate wound healing via stimulating proliferation of regulatory T cells (a subset of T lymphocytes that function to suppress potentially harmful immune responses) and M2‐like macrophage polarization (the anti‐inflammatory phenotype of macrophages). [ 87–89 ] The ability of regulatory T cells to suppress deleterious inflammation may represent a pathway by which commensal and probiotic bacteria maintain healthy immune interactions, thereby avoiding damaging pro‐inflammatory states.…”