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

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 9

BM alterations underlie the protective effect of parasite infection.

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BM alterations underlie the protective effect of parasite infection. (A ...
(A and B) Data obtained following BM adoptive transfer experiments. Mice received BM cells from FcγRIIb-KO uninfected (BM Ctrl) or infected (BM Py) donors. (A) Percentage of mice with various levels of proteinuria as indicated in grayscale. Dead mice are shown in black. n = 14 (months 2–4) and n = 12 (months 5–6). (B) Absolute number of infiltrating leukocytes in the kidney or liver, with each immune cell population indicated by the color scheme, 5 months after BM transfer. n = 2 and n = 5 for the WT and FcγRIIb-KO groups. (C–G) Chimera assay. Data were obtained following BM adoptive transfer experiments indicated in the scheme in C. Mice received BM cells from FcγRIIb-KO CD45.1 uninfected or infected donors or Py/control mixed chimeric mice (BM chimera). (D) Graphs show the reconstitution of donor cells (CD45.1) in the indicated organs. (E) Number of infiltrating leukocyte subpopulations in the kidneys 6 months after BM transfer. n = 2, 3, 2, and 4 for WT, BM control, Py-infected, and chimeric mice, respectively. (F) Frequency of CD45.1+ T cells (CD45+CD3+), neutrophil/monocytes (CD11b+Ly6C/G+), macrophages (CD11b+Ly6C/G–F4/80+), and DCs (CD11b+Ly6C/G–F4/80–SSClo). n = 4. (G) Flow cytometry gating strategy. Data are presented as the mean ± SD. Group comparisons were made using 1- and 2-way ANOVA. *P < 0.05 and ***P < 0.001. Macro, macrophages; Neu/Mon, neutrophils/monocytes.