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Plasmacytoid dendritic cells promote acute kidney injury by producing interferon-α.

ABSTRACT: Acute kidney injury (AKI) is a common clinical complication associated with high mortality in patients. Immune cells and cytokines have recently been described to play essential roles in AKI pathogenesis. Plasmacytoid dendritic cells (pDCs) are a unique DC subset that specializes in type I interferon (IFN) production. Here, we showed that pDCs rapidly infiltrated the kidney in response to AKI and contributed to kidney damage by producing IFN-α. Deletion of pDCs using DTR^BDCA2 transgenic (Tg) mice suppressed cisplatin-induced AKI, accompanied by marked reductions in proinflammatory cytokine production, immune cell infiltration and apoptosis in the kidney. In contrast, adoptive transfer of pDCs during AKI exacerbated kidney damage. We further identified IFN-α as the key factor that mediated the functions of pDCs during AKI, as IFN-α neutralization significantly attenuated kidney injury. Furthermore, IFN-α produced by pDCs directly induced the apoptosis of renal tubular epithelial cells (TECs) in vitro. In addition, our data demonstrated that apoptotic TECs induced the activation of pDCs, which was inhibited in the presence of an apoptosis inhibitor. Furthermore, similar deleterious effects of pDCs were observed in an ischemia reperfusion (IR)-induced AKI model. Clinically, increased expression of IFN-α in kidney biopsies was observed in kidney transplants with AKI. Taken together, the results of our study reveal that pDCs play a detrimental role in AKI via IFN-α.

SUBMITTER: Deng B

PROVIDER: S-EPMC7852581 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Rigid interferon-alpha subtype responses of human plasmacytoid dendritic cells.

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Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus.

Project description:IntroductionPlasmacytoid dendritic cells (pDCs) constitutively express two members of the Toll-like receptor (TLR) family, TLR-9 and TLR-7, through which they can be stimulated to produce high levels of interferon (IFN)-?, a key mediator of the pathogenesis of systemic lupus erythematosus (SLE). Given the known efficacy of hydroxychloroquine (HCQ) in the treatment of SLE, we examined its ability to inhibit such pDC function in vivo.MethodsPeripheral blood mononuclear cells (PBMCs) from SLE subjects treated or not with HCQ and from healthy controls were stimulated with the TLR-9 agonist, CpG oligodeoxynucleotides (CpG-A ODN)-2216, and the TLR-7 agonist, imiquimod. The proportion of monocytes, B cells, myeloid dendritic cells, pDCs, and natural killer (NK) cells producing IFN-? and tumor necrosis factor alpha (TNF-?) was then analyzed by multiparameter flow cytometry.ResultsAfter TLR-9/7 stimulation in both SLE and healthy subjects, significant production of IFN-? and TNF-? was only observed in pDCs. TLR-7 and TLR-9 induced IFN-? and TNF-? production by pDCs from subjects with SLE was decreased relative to that found in controls (TLR-9/IFN-?, P < 0.0001; TLR-9/TNF-? P < 0.0001; TLR-7/TNF-? P = 0.01). TLR-9 and TLR-7 induced IFN-? and TNF-? production by pDCs was severely impaired in 36% (TLR-9) and 33% (TLR-7) of SLE subjects. In almost all cases, these subjects were being treated with HCQ (HCQ vs. no HCQ: impaired TLR-9/IFN-?, P = 0.0003; impaired TLR-7/IFN-?, P = 0.07; impaired TLR-9/TNF-?, P < 0.009; impaired TLR-7/TNF-?, P < 0.01).ConclusionsTreatment with HCQ is associated with impaired ability of pDCs from subjects with SLE to produce IFN-? and TNF-? upon stimulation with TLR-9 and TLR-7 agonists.

| S-EPMC3446541 | biostudies-literature

Increased Abundance of Plasmacytoid Dendritic Cells and Interferon-Alpha Induces Plasma Cell Differentiation in Patients of IgA Nephropathy.

Project description:The roles of pDC and IFN-? have not been well defined in IgA nephropathy (IgAN). In this study, we investigated the abundance of pDCs and IFN-? in IgAN patients and the response of peripheral blood mononuclear cells (PBMCs) after stimulation of the pDC-preferred TLR9 ligand CpG2216. The effects of IFN-? on plasma cell differentiation and leukocyte migration were also investigated. Here, we found that the percentages of pDCs were increased in PBMCs of IgAN patients, than in those of healthy controls. Plasma levels of IFN-? proteins and abundance of plasma cells were higher in IgAN patients than in healthy donors. Plasma IFN-? levels were positively associated with proteinuria, renal IgM deposition, and renal tubular atrophy/interstitial fibrosis grade in IgAN patients. Ex vivo activation of TLR9 on pDCs resulted in increased IFN-? production and enhanced plasma cell differentiation in IgAN patients as compared with healthy donors. IFN-? treatment led to increased plasma cell differentiation in vitro. IFN-? also significantly promoted expression of chemokines IP-10 and MCP-1 in human mesangial cells, which subsequently facilitated the transendothelial migration of human CD4+ and CD14+ cells. In conclusion, pDC and its secreted cytokine IFN-? may play important roles in pathological changes of IgA nephropathy.

| S-EPMC5748321 | biostudies-literature

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