Intracapillary immune complexes recruit and activate slan-expressing CD16+ monocytes in human lupus nephritis
Florina Olaru, Thomas Döbel, Anke S. Lonsdorf, Stephanie Oehrl, Michael Maas, Alexander H. Enk, Marc Schmitz, Elisabeth F. Gröne, Hermann-J. Gröne, Knut Schäkel
Florina Olaru, Thomas Döbel, Anke S. Lonsdorf, Stephanie Oehrl, Michael Maas, Alexander H. Enk, Marc Schmitz, Elisabeth F. Gröne, Hermann-J. Gröne, Knut Schäkel
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Research Article Immunology

Intracapillary immune complexes recruit and activate slan-expressing CD16+ monocytes in human lupus nephritis

Abstract

Lupus nephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Among the different types of lupus nephritis, intracapillary immune complex (IC) deposition and accumulation of monocytes are hallmarks of lupus nephritis class III and IV. The relevance of intracapillary ICs in terms of monocyte recruitment and activation, as well as the nature and function of these monocytes are not well understood. For the early focal form of lupus nephritis (class III) we demonstrate a selective accumulation of the proinflammatory population of 6-sulfo LacNAc+ (slan) monocytes (slanMo), which locally expressed TNF-α. Immobilized ICs induced a direct recruitment of slanMo from the microcirculation via interaction with Fc γ receptor IIIA (CD16). Interestingly, intravenous immunoglobulins blocked CD16 and prevented cell recruitment. Engagement of immobilized ICs by slanMo induced the production of neutrophil-attracting chemokine CXCL2 as well as TNF-α, which in a forward feedback loop stimulated endothelial cells to produce the slanMo-recruiting chemokine CX3CL1 (fractalkine). In conclusion, we observed that expression of CD16 equips slanMo with a unique capacity to orchestrate early IC-induced inflammatory responses in glomeruli and identified slanMo as a pathogenic proinflammatory cell type in lupus nephritis.

Authors

Florina Olaru, Thomas Döbel, Anke S. Lonsdorf, Stephanie Oehrl, Michael Maas, Alexander H. Enk, Marc Schmitz, Elisabeth F. Gröne, Hermann-J. Gröne, Knut Schäkel

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Figure 6

IC-slanMo interaction mediates inflammatory responses.

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IC-slanMo interaction mediates inflammatory responses. (A) Single-color ...
(A) Single-color images and combined colors for the detection of TNF-α (green), slanMo (red), and cell nuclei (DAPI; blue) in lupus nephritis glomeruli class III. Original magnification, ×20. Results are representative of multiple sections from 3 independent donors (n = 3). Asterisks indicate double-positive cells. (B) Cytokine induction by immobilized immune complexes (ICs). Freshly isolated slanMo were treated or not with Syk inhibitor or specific blocking mAbs for CD16 (3G8) and incubated with immobilized ICs for 20 hours. TNF-α, IL-6, and CXCL2 protein levels in the culture medium were determined by ELISA (n = 3). (C) TNF-α and IL-6 levels in the culture medium of CD1c+ DCs and monocytes in the presence or absence of immobilized ICs (n = 3). (D) HDMECs were cultured for 20 hours with supernatants from slanMo previously incubated with immobilized ICs and in the presence or absence of a neutralizing TNF-α mAb (10 μg/ml). CX3CL1 protein levels were determined by ELISA (n = 3). Mean values are shown ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA followed by Bonferroni’s multiple-comparison test.