Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35

Koda, Yuzo; Nakamoto, Nobuhiro; Chu, Po–Sung; Ugamura, Aya; Mikami, Yohei; Teratani, Toshiaki; Tsujikawa, Hanako; Shiba, Shintaro; Taniki, Nobuhito; Sujino, Tomohisa; Miyamoto, Kentaro; Suzuki, Takahiro; Yamaguchi, Akihiro; Morikawa, Rei; Sato, Katsuaki; Sakamoto, Michiie; Yoshimoto, Takayuki; Kanai, Takanori

doi:10.1172/jci125863

Cited by 34 publications

(30 citation statements)

References 45 publications

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“…In most studies, Tregs were found to proliferate and show protective effects at 7 days post MCAO or even later, and only a very low number of Tregs were observed within the first week after transient ischemia (Gelderblom et al, 2009;Stubbe et al, 2013;Liesz and Kleinschnitz, 2016), which implied that it seems to be questionable if the protective effects of pDCs are directly mediated via Tregs. In our study, we found that under physiological condition, 120G8 induced the downtrend of cerebral Tregs and obviously reduced the splenic and blood Tregs, which inferred that the pDCs depletion oriented the systemic pro-inflammation and pDCs protecting against ischemic brain injury may be realized by maintaining the systemic immune homeostasis, which is consistent with the notion that pDCs are in association with Tregs, serving as a guide for immunotherapeutic options in acute liver failure (Koda et al, 2019).…”

Section: Discussionsupporting

confidence: 86%

Plasmacytoid Dendritic Cells Protect Against Middle Cerebral Artery Occlusion Induced Brain Injury by Priming Regulatory T Cells

Chen

Chencheng

Liu

et al. 2020

Front. Cell. Neurosci.

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Regulatory T cells (Tregs) play an anti-inflammatory effect to protect against ischemic stroke. Plasmacytoid dendritic cells (pDCs) can induce regulatory T cells tolerance in sterile-inflammation conditions. However, whether and how pDCs-mediated Tregs response play a part in the pathology of ischemic stroke remains unclear. In this study, we showed that pDCs were increased in the brain of middle cerebral artery occlusion (MCAO) mice. Depletion of pDCs with 120G8 exacerbated MCAO-induced brain injury, peripheral pro-inflammation response and decreased the systemic Tregs in mice. Furthermore, the data of mixed lymphocyte reaction (MLR) in vitro demonstrate that splenic pDCs from MCAO mice can significantly promote Tregs proliferation, accompanying with the increased expression of indoleamine 2,3-dioxygenase 1 (IDO1) on pDCs. Taken together, the findings here suggested that under the pathologic state of stroke, pDCs protect against MCAO-induced brain injury by priming Tregs, illustrating that pDCs represented as a therapeutic target for the prevention of ischemic brain injury.

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Section: Discussionsupporting

confidence: 86%

Plasmacytoid Dendritic Cells Protect Against Middle Cerebral Artery Occlusion Induced Brain Injury by Priming Regulatory T Cells

Chen

Chencheng

Liu

et al. 2020

Front. Cell. Neurosci.

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“…Additionally, a protein construct with covalently linked EBi3 and p35 inhibited the proliferation of CD4 + CD25 ‐ T effector cells and differentiation of Th17 cells in vitro, yet expanded CD4 + CD25 + Tregs 90 . Following these studies describing the suppressive role of IL‐35 secreted by Tregs, IL‐35 production was detected in other cell types, including dendritic cells, B cells, and cancer cells 69,92‐97 . IL‐35 expression has been found in several human cancers 92,96,98‐102 .…”

Section: Immunosuppressive Functions Of B Cells In Preclinical Cancermentioning

confidence: 99%

Regulatory B cells in cancer

Michaud

Steward

Mirlekar

et al. 2020

Immunological Reviews

115

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Tumorigenesis proceeds through discrete steps where acquisition of genetic lesions and changes in the surrounding microenvironment combine to drive unrestricted neoplastic proliferation and metastasis. The ability of tumor‐infiltrating immune cells to promote tumor growth via the provision of signals that enable tumor cell survival and proliferation as well as contribute to immune suppression is an active area of research. Recent efforts have provided us with mechanistic insights into how B cells can positively and negatively regulate immune responses. Negative regulation of immune responses in cancer can be mediated by regulatory B cells and is often a result of increased production of cytokines that can directly and indirectly affect anti‐tumor immune function and cancer cell growth. Signals that lead to the expansion of regulatory B cells and the spectrum of their functional roles are not well understood and are the subject of active research by many groups. Here, we elaborate broadly on the history of regulatory B cells in cancer and summarize recent studies that have established genetic models for the study of regulatory B cell function and their potential for therapeutic intervention in the setting of solid cancers.

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“…In this study, we showed two constitutive subunits of IL-35 (EBI3 and p35) mRNA and protein were strikingly upregulated in lung tissues from HySu-induced experimental PH mice, and mice serum IL-35 levels were elevated after exposure to HySu. Recent investigations have indicated that IL-35 can be expressed in Tregs, macrophages, and dendritic cells (7,35,36). Concurrent with the results of immunofluorescence staining in the existing research, IL-35 was mainly derived from regulatory T cells, rather than macrophages and dendritic cells, in HySuinduced pulmonary hypertensive mice.…”

Section: Discussionmentioning

confidence: 60%

Tregs-derived interleukin 35 attenuates endothelial proliferation through STAT1 in pulmonary hypertension

et al. 2021

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Background: To explore the source, the role and the specific mechanism of IL-35 and its downstream molecules in the development of pulmonary hypertension.Methods: 8-10 weeks male mice were undergoing hypoxia combined with SU5416 (HySu) to establish a pulmonary hypertension (PH) model. The phenotype of PH mice was measured by immunohistochemistry and immunofluorescence staining. The levels of two subunits (EBI3 and p35 subunits) in lung tissue were measured by real-time PCR and western blotting. EBI3 monoclonal antibody was administrated as IL-35 neutralization to offset systemic IL-35 expression. Fludarabine, an inhibitor of STAT1 (signal transducer and activator of transcription 1) was used to clarify the role of STAT1 under IL-35 treatment. Results: After pulmonary hypertension, the expression of IL-35 and its two subunits (EBI3 and p35 subunits) in lung tissue were significantly increased. And the two subunits of IL-35 are highly expressed in Treg cells. Compared with the controlled PH mice, the IL-35 neutralization PH mice showed aggravated pulmonary hypertension phenotype. The specific manifestations are the increase of right ventricular systolic pressure (RVSP), the growing proportion of right heart [RV/(LV+S)], and the remodeling of pulmonary blood vessels increases. The expression of pulmonary vascular endothelium (CD31) in PH mice increased, and the proliferation ability of vascular endothelium enhanced after IL-35 was inhibited. IL-35 phosphorylates STAT1 through the receptor GP130 on pulmonary vascular endothelial cells, which in turn inhibits endothelial cell proliferation. IL-35 recombinant protein can reduce the expression of CD31 in lung tissues of PH mice. But the administration of STAT1 inhibitor made it invalid from the IL-35 effect of reversing pulmonary hypertension. Conclusions: Tregs-derived IL-35 can reverse the remodeling of pulmonary blood vessels and alleviate the progression of pulmonary hypertension by reducing the proliferation of endothelial cells.

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Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35

Cited by 34 publications

References 45 publications

Plasmacytoid Dendritic Cells Protect Against Middle Cerebral Artery Occlusion Induced Brain Injury by Priming Regulatory T Cells

Plasmacytoid Dendritic Cells Protect Against Middle Cerebral Artery Occlusion Induced Brain Injury by Priming Regulatory T Cells

Regulatory B cells in cancer

Tregs-derived interleukin 35 attenuates endothelial proliferation through STAT1 in pulmonary hypertension

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