Immune complex (IC) deposition in the vascular bed is thought to contribute to pathogenic events of autoimmunity-driven inflammatory diseases. Lupus nephritis is an immune complex (IC)-mediated disease that is affecting the kidneys and develops as a frequent complication of systemic lupus erythematosus (SLE). Here, we recognized that human kidney sections of lupus nephritis contained TNF-α-positive 6-sulfo LacNAc dendritic cells (slanDCs), a subset of highly proinflammatory dendritic cells (DC) previously characterized by an outstanding capacity to bind ICs. To investigate the role of ICs in the recruitment of slanDCs we set up a mouse model of IC-deposition in glomeruli. Using this model we observed an IC-dependent recruitment of slanDCs in the glomeruli, which was dependent on Fc gamma receptor IIIA (FcγRIII, CD16). This was confirmed in vitro by using a perfusion assay-based approach which demonstrates under conditions matching the blood flow of venous capillaries that slanDCs but not plasmacytoid DCs, CD1c+ DCs or T cells are efficiently recruited from the flow by immobilized ICs. Under all tested conditions the attachment of slanDCs was dependent on FcγRIII. Cross-linking of FcγRIII on slanDC by ICs induced the neutrophil recruiting chemokine CXCL2, as well as TNF-α which in a feed forward signal to endothelial cells induced the slanDC and T cell recruiting chemokine CX3CL1. Taken together, our data provide evidence regarding new mediators and mechanisms of recruitment of inflammatory cells in lupus nephritis. Modulation of FcgRIII/ICs-mediated slanDCs recruitment may offer therapeutic benefits in patients with lupus nephritis.

Immune complexes recruit and activate proinflammatory human slanDC in lupus nephritis