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.
View: Text | PDF
Research Article Autoimmunity Nephrology Article has an altmetric score of 6

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

×

Figure 1

Parasite infection induces autoreactivity while reducing kidney pathology.

Options: View larger image (or click on image) Download as PowerPoint
Parasite infection induces autoreactivity while reducing kidney patholog...
(A) Schematic representation of the experimental design and timeframes applicable throughout the study (further details are presented in Supplemental Figure 1, A and B). (B–E) Cumulative survival curve and percentage of FcγRIIb-KO (FcγRIIb[KO]) mice and WT mice with the indicated levels of proteinuria following a double (B and C) or single (D and E) infection with Py. The time point of Py infection is indicated by arrows (n = 5 and n = 10 in the survival analysis). Proteinuria levels were measured by chemical strips and are shown in grayscale. (C) n = 14 (months 1–6), n = 9 (months 7–8), and n = 7 (month 9). (E) n = 7 and n = 15–22 for the WT and FcγRIIb-KO groups, respectively. (F) ANA detection in serum of WT or FcγRIIb-KO mice infected with Py at 2 months of age. Shown are representative images of the immunofluorescence assay (original magnification, ×20) and graphs indicating the percentage of mice with the indicated ANA levels. ANA positivity in different serum dilutions is shown in grayscale. n = 7 in WT and n = 22 for the FcγRIIb-KO groups (months 0–2), and n = 5 for the WT and n = 14 for the FcγRIIb-KO groups (months 3–4). (G) Representative H&E-stained images (scale bars: 1 mm [top] and 500 μm [bottom]) and spleen weights for WT (n = 6) and FcγRIIb-KO (n = 17) mice 5 months after a single infection with Py. (H) Serum cytokine levels (IFN-γ, IL-12p70, MCP-1, IL-10, IL-6, and TNF) measured 1 and 5 months after a single Py infection. Genotype and infection status are indicated in G. n = 4 and n = 10 for the WT and FcγRIIb-KO groups. Data are presented as the mean ± SD. *P < 0.05, **P < 0.01, and ****P < 0.0001, by log-rank (Mantel-Cox) test was used for survival comparisons (B and D) and 1- and 2-way ANOVA (G and H). Ctrl, control.