Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis
Jeeba Kuriakose, … , Peter Vogel, Hans Häcker
Jeeba Kuriakose, … , Peter Vogel, Hans Häcker
Published April 29, 2019
Citation Information: J Clin Invest. 2019;129(6):2251-2265. https://doi.org/10.1172/JCI125116.
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Research Article Inflammation

Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with genetic and environmental contributions. Hallmarks of the disease are the appearance of immune complexes (IC) containing autoreactive Abs and TLR-activating nucleic acids, whose deposition in kidney glomeruli is suspected to promote tissue injury and glomerulonephritis (GN). Here, using a mouse model based on the human SLE susceptibility locus TNFAIP3-interacting protein 1 (TNIP1, also known as ABIN1), we investigated the pathogenesis of GN. We found that GN was driven by TLRs but, remarkably, proceeded independently of ICs. Rather, disease in 3 different mouse models and patients with SLE was characterized by glomerular accumulation of patrolling monocytes (PMos), a cell type with an emerging key function in vascular inflammation. Consistent with such function in GN, monocyte-specific deletion of ABIN1 promoted kidney disease, whereas selective elimination of PMos provided protection. In contrast to GN, PMo elimination did not protect from reduced survival or disease symptoms such as IC generation and splenomegaly, suggesting that GN and other inflammatory processes are governed by distinct pathogenic mechanisms. These data identify TLR-activated PMos as the principal component of an intravascular process that contributes to glomerular inflammation and kidney injury.

Authors

Jeeba Kuriakose, Vanessa Redecke, Cliff Guy, Jingran Zhou, Ruiqiong Wu, Sirish K. Ippagunta, Heather Tillman, Patrick D. Walker, Peter Vogel, Hans Häcker

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Figure 7

Cell-intrinsic function of ABIN1 controls the development and inflammatory phenotype of PMos.

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Cell-intrinsic function of ABIN1 controls the development and inflammato...
(A and B) Relative numbers of CD43+ PMos derived from Tnip1+/+ and Tnip1–/– Hoxb8-FL cells in (A) PB and (B) kidneys 11 days after adoptive transfer of Hoxb8-FL cells (detailed in Methods). (C) Relative numbers of Tnip1–/– and Tnip1-reconstituted (+ Tnip1) Ly6G+ neutrophils (left), Ly6Chi monocytes (middle), and CD43+ PMos (right) derived from the Hoxb8-FL cells described in A. Data on cells isolated from kidneys 8 days after adoptive transfer of Hoxb8-FL cells are shown. (D) Relative numbers of PMos in PB blood from BM chimeras (6 weeks after transfer), which were established from Tnip1+/+ and Tnip1–/– mice or from Tnip1–/– and Tnip1–/– Myd88–/– mice as indicated. (E) Quantitative PCR analysis of PMos that were FACS sorted from kidneys of BM-chimeric mice, based on BM from Tnip1+/+ and Tnip1–/– mice as indicated (25 weeks after BM transfer). Data represent the mean ± SD. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by Mann-Whitney U test (A–D) and unpaired t test (E). Symbols represent data from individual mice.