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CCL17-producing cDC2s are essential in end-stage lupus nephritis and averted by a parasitic infection
Laura Amo, … , Juan Wu, Silvia Bolland
Laura Amo, … , Juan Wu, Silvia Bolland
Published June 1, 2021
Citation Information: J Clin Invest. 2021;131(11):e148000. https://doi.org/10.1172/JCI148000.
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Research Article Autoimmunity Nephrology

CCL17-producing cDC2s are essential in end-stage lupus nephritis and averted by a parasitic infection

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Abstract

Lupus nephritis is a severe organ manifestation in systemic lupus erythematosus leading to kidney failure in a subset of patients. In lupus-prone mice, controlled infection with Plasmodium parasites protects against the progression of autoimmune pathology including lethal glomerulonephritis. Here, we demonstrate that parasite-induced protection was not due to a systemic effect of infection on autoimmunity as previously assumed, but rather to specific alterations in immune cell infiltrates into kidneys and renal draining lymph nodes. Infection of lupus-prone mice with a Plasmodium parasite did not reduce the levels or specificities of autoreactive antibodies, vasculitis, immune complex–induced innate activation, or hypoxia. Instead, infection uniquely reduced kidney-infiltrating CCL17-producing bone marrow–derived type 2 inflammatory dendritic cells (iDC2s). Bone marrow reconstitution experiments revealed that infection with Plasmodium caused alterations in bone marrow cells that hindered the ability of DC2s to infiltrate the kidneys. The essential role for CCL17 in lupus nephritis was confirmed by in vivo depletion with a blocking antibody, which reduced kidney pathology and immune infiltrates, while bypassing the need for parasitic infection. Therefore, infiltration into the kidneys of iDC2s, with the potential to prime local adaptive responses, is an essential regulated event in the transition from manageable glomerulonephritis to lethal tubular injury.

Authors

Laura Amo, Hemanta K. Kole, Bethany Scott, Chen-Feng Qi, Juan Wu, Silvia Bolland

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Figure 8

Parasite infection inhibits kidney disease by reducing CCL17-expressing DCs.

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Parasite infection inhibits kidney disease by reducing CCL17-expressing ...
Analysis of DCs from FcγRIIb-KO mice 5 months after infection with Py. (A) Number of conventional DCs (cDCs) (CD11b+CD11chiMHC-II+) in the spleen and axillary, inguinal, and renal LNs relative to numbers of DCs from FcγRIIb-KO controls (n = 5). (B) Dot plots showing the gating of DCs (in red) in renal LNs. (C) Flow cytometric measurements of DCs in the kidneys. Graphs show the frequency of myeloid (CD45+CD11b+) and DCs (CD45+CD11b+CD11chiMHC-IIhi) among total kidney cells acquired, the percentage of DCs among CD11b+ cells, and the number of DCs in the kidneys (n = 4). (D) Representative dot plot showing the gating of DCs within the kidney-infiltrating CD11b+ cell population. (E) CD11c staining in kidney sections from the indicated mice (scale bar: 200 μm). (F) Intracellular expression of CCL17 measured in CD11chi kidney-infiltrating DCs (n = 4). FcγRIIb-KO controls (light gray); expression in samples after Py infection (dark gray). (G) Correlation of Ccl17 expression measured by qPCR with the number of DCs. Left: The regression curve was obtained with serial dilutions of BM-derived DCs grown in culture. Right: Estimate of the number of DCs that theoretically corresponded to the CCL17 levels detected in the kidney of mice with the indicated genotype and infection status (n = 4). CT, cycle threshold in CCL17 mRNA qPCR testing. (H) Correlation graphs showing Ccl7 gene expression levels in CD11b+ cells versus the percentage of DCs or expression of CCL17 measured by flow cytometry in the same FcγRIIb-KO control mice (Pearson’s r = 0.869 and 0.877, 2-tailed approximate P value **P < 0.01, n = 8). (I) Surface marker characterization of kidney DCs (CD11b+CD11chiCD26+) (blue), macrophages (CD11b+CD11c+CD26–) (red), and CD11b– cells (gray). Data are presented as the mean ± SD. Group comparisons were made using a 1-sample t test and the Mann-Whitney U test. *P < 0.05 and ***P < 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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