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 6

Parasite infection reduces the leukocyte-attracting chemokines CCL20 and CCL17 in the kidney without affecting innate cytokines and chemokines.

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Parasite infection reduces the leukocyte-attracting chemokines CCL20 and...
(A–E) Gene expression studies in kidneys of FcγRIIb-KO mice 5 months after infection with Py. (A) mRNA expression of the indicated genes in bead-purified kidney leukocytes (CD45+) and nonimmune cells (CD45–). Results are relative to Actb expression (n = 4). (B) Gene expression analysis of total kidney RNA using the Cytokines & Chemokines RT2 Profiler PCR Array kit. Scatter plots show the fold change between WT infected versus control, FcγRIIb-KO infected versus control, and WT versus FcγRIIb-KO mice. Red and green colors represent higher or lower expression compared with the control (n = 3). (C) Resulting fold change in expression of Ccl17 and Ccl20 genes compared with expression in WT control mice. (D) Expression of the indicated chemokines in leukocytes (CD45+), myeloid (CD11b+) cells, sorted infiltrating CD4+ T cells, and kidney nonimmune cells (CD45–) (n = 4). (E) Graphs showing the correlation of Ccl17 expression in CD11b+ cells and Ccl20 expression in CD45– cells to proteinuria levels in FcγRIIb-KO control mice (R2 = 0.96 and 0.56, respectively). (F) Liver expression of the indicated chemokine genes (n = 4). Data are presented as the mean ± SD. Group comparisons were made using 1- and 2-way ANOVA. *P < 0.05 and **P < 0.01.