(B) The mean number of immunohistochemically identified slanMo in glomeruli found in kidney samples of patients with lupus nephritis: healthy (= 14), class I (= 8), class II (= 4), III (= 22), IV (= 18) or V (= 12)

(B) The mean number of immunohistochemically identified slanMo in glomeruli found in kidney samples of patients with lupus nephritis: healthy (= 14), class I (= 8), class II (= 4), III (= 22), IV (= 18) or V (= 12). 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-, which in a forward feedback loop stimulated endothelial cells to produce the slanMo-recruiting chemokine CX3CL1 (fractalkine). In conclusion, we GSK484 hydrochloride 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. Keywords: Autoimmunity, Immunology Keywords: Monocytes Slan-expressing CD16+ monocytes orchestrate immune complex-induced inflammatory responses in glomeruli of lupus nephritis patients. Introduction A number of diseases are associated with the deposition of immune complexes (ICs) in the vascular bed, the production of antibodies against the vascular basement membrane or endothelial cells, which can lead to vasculitis or glomerulonephritis (1C3). The etiology of IC formation can be either autoimmune (systemic lupus erythematosus, Goodpasture syndrome), infectious (postinfectious glomerulonephritis), or a humoral rejection of an allogeneic transplant. In these conditions ICs are formed and can be found in the walls of capillaries of the renal glomerulus, like in lupus nephritis (4), or other locations depending on the disease type resulting in local tissue injury and deterioration of endothelial function. Further, the local deposition of ICs can lead to activation of myeloid cells through their Fc receptors (FcRs) (5C7). Depending on the FcR repertoire, monocytes, macrophages, granulocytes, and dendritic cells (DCs) execute a broad spectrum of effector functions or are modulated in their activity by the presence of ICs (8). Studies in mice proposed that activation of myeloid cells by glomerular deposits of ICs requires both FcR and TLRs (9, 10), which initiates an inflammatory response that results in glomerulonephritis (10). In stage III and IV lupus nephritis with capillary GSK484 hydrochloride deposition of ICs, FcRIIIA+ (CD16+) monocytes were noticed and regarded as relevant to the pathogenesis of the disease (11). Monocytes are now classified based on their gradual differences in CD14 versus CD16 expression: classical CD14++CD16C, intermediate CD14+CD16+, and nonclassical CD14CCD16++ monocytes (12). Within the GSK484 hydrochloride population of CD16+LINCHLA-DR+ leukocytes (nonclassical CD14CCD16++ monocytes) GSK484 hydrochloride our group defined the population of 6-sulfo LacNAcCexpressing monocytes (slanMo). Roughly half of the nonclassical monocytes stain positive for slan (Supplemental Physique 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.96492DS1). The marker molecule slan allowed the mAb-directed purification and FACD functional studies of these cells purified from blood and tonsils, which revealed functional characteristics of DCs (13C14). Most notably, slanMo showed a strong capacity to stimulate T cells and to program Th1/Th17 cells (15C17). DCs, monocytes, and macrophages are now classified based on their identified precursor cell. For slan+ cells, transcriptomic studies collectively exhibited a gene signature shared with monocytes rather than bona fide DCs (18). We therefore propose calling these cells slanMo instead of slanDCs, as already recommended by others (19). The larger population of human nonclassical monocytes is regarded as equivalent to GSK484 hydrochloride mouse patrolling monocytes (20). These patrolling CX3CR1hiLy6Clo monocytes are guardians of the intravascular immune surveillance that showed a prolonged contact with the endothelium and orchestrate the phagocytosis of cellular debris (21). They were seen constitutively in uninflamed glomeruli (22). Prolonged interactions with the endothelial cells were found when inflammation was artificially induced by antibodies directed against endothelial cells of the glomerular capillaries. Subsequent contact with neutrophils promoted acute neutrophil-dependent glomerular injury, suggesting the crucial role of murine monocytes in inflammatory glomerular diseases (23). A similar picture with neutrophil recruitment was observed when patrolling monocytes were activated by TLR7-dependent nucleic acid danger signals (21). The presence of CD16+ monocytes in human lupus nephritis with capillary IC deposition (stage IV) correlated with endothelial CX3CL1 (fractalkine) expression, which may have contributed to their recruitment (11). In this study, we sought the identity of the monocytic cells in human lupus nephritis and their pathogenic role, with special reference to their direct recruitment from the blood circulation in the context of immobilized ICs. We previously reported an increased frequency of slanMo in the dermis of lupus skin lesions (24). In patients with systemic lupus erythematosus, ICs circulate in blood and are deposited in different organs where they contribute to organ failure. IC deposition on the surface of the glomerular.

tuskonus