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 7

Depletion of the chemokine CCL17 reduces severe glomerulonephritis.

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Depletion of the chemokine CCL17 reduces severe glomerulonephritis. (A–C...
(A–C) Long-term depletion of CCL17 and CCL20 chemokines in FcγRIIb-KO. Two-month-old mice were injected i.v. with 20 μg IgG2a (isotype control) or CCL17 or CCL20 antibodies, 3 times per month for the duration of the experiment. (A) Proteinuria levels and ANA scores monthly after the first injection (n = 3). ANA scores were determined by positive IgG staining in different serum dilutions: ANA score of 1 (1:100), ANA 2 (1:300), ANA 3 (1:900), ANA 4 (1:2700), and ANA 5 (1:8100). (B) Number of infiltrating cells in the kidneys 5 months after the first injection. (C) Number of cells in the spleen, axillary LNs, renal LNs and infiltrated into the kidneys for all groups. n = 2 for WT mice and n = 3 in the indicated FcγRIIb-KO injected mice. (D–F) Short-term depletion of CCL17 in FcγRIIb-KO mice with ongoing glomerulonephritis. Mice at 7.5 months of age were injected i.v. with 25 μg IgG2a or CCL17 on days 0, 4, 8, and 12. (D) Mice were selected on the basis of similar proteinuria levels, as measured by QuantiChrom colorimetric assay. (E) Number of cells in renal LNs and infiltrated into the kidney. (F) Subpopulations of cells detected by flow cytometry on day 18. n = 1 for WT and n = 5 for FcγRIIb-KO groups. Data are presented as the mean ± SD. Group comparisons were made using 1- and 2-way ANOVA. *P < 0.05. α, anti.