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 3

Parasite infection prevents severe kidney injury but does not reduce glomerular inflammation in FcγRIIb-KO mice.

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Parasite infection prevents severe kidney injury but does not reduce glo...
Study of kidney pathology in WT and FcγRIIb-KO mice 5 months after infection with Py. (A) Representative images of kidney sections stained with H&E (n = 6), PAMS (n = 4), and TUNEL (n = 2) (scale bars: 100 μm) and TEM images (n = 5) (scale bar: 1 μm). Yellow arrows in the PAMS images indicate noticeable basement membrane abnormalities. Yellow arrows in the TEM images indicate intact (WT control and FcγRIIb-KO Py) and destroyed (FcγRIIB-KO control) podocyte foot processes. (B) ImageJ measurements of glomerular and Bowman’s space areas (each dot represents 1 glomerulus; n = 2 WT and n = 5 FcγRIIb-KO mice per group), percentage of sclerotic glomeruli, interstitial infiltration, and protein deposit areas in the kidneys (each dot represents 1 mouse). n = 3 and n = 14 (sclerotic glomeruli); n = 6 and n = 14 (interstitial infiltration) for the WT and FcγRIIb-KO groups, respectively. (C) NIH activity and chronicity indexes calculated as described in Supplemental Figure 3B. n = 4, 2, 10, and 10 for WT control, WT Py, FcγRIIb-KO control and FcγRIIb-KO Py, respectively. Data are presented as the mean ± SD. FcγRIIb-KO comparisons were made using the Kruskal-Wallis test. *P < 0.05, **P < 0.01, and ****P < 0.0001.