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 4

Recruitment of slanMo from the flow requires expression of CD16.

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Recruitment of slanMo from the flow requires expression of CD16. (A) CD1...
(A) CD16-specific capture of slanMo by immobilized immune complexes (ICs). Freshly isolated slanMo were labeled for fluorescence microscopic detection and incubated with specific blocking mAbs for CD16 (3G8), CD32 (AT10), or both as well as a binding (DX17) and a nonbinding (MOPC-21) isotype control. Additionally, intravenous immunoglobulin (IVIG) was used for blocking FcγR. SlanMo subsequently were perfused over immobilized ICs for 30 minutes with an applied surface shear stress of 0.5 dyn/cm2 (n = 4). (B) Freshly isolated and CD16-negative mature slanMo of the same donor run over immobilized ICs for 30 minutes at a shear stress of 0.5 dyn/cm2 (n = 3). The histograms give an example of the CD16 expression of freshly isolated and mature slanMo of the same donor. (C) CD16a-transfected, CD32a-transfected, and nontransfected Jurkat cells were fluorescently labeled and subsequently run over immobilized ICs for 30 minutes at a shear stress of 0.5 dyn/cm2 (n = 3). Mean values are shown ± SEM. ***P < 0.001. ns, not significant by 1-way ANOVA followed by Tukey’s post hoc test.