Phenotype, Function, and Mobilization of 6-Sulfo LacNAc-Expressing Monocytes in Atopic Dermatitis

Abstract

Mononuclear phagocytes (MPs) are important immune regulatory cells in atopic dermatitis (AD). We previously identified 6-sulfo LacNAc-expressing monocytes (slanMo) as TNF-α- and IL-23-producing cells in psoriatic skin lesions and as inducers of IFN-γ-, IL-17-, and IL-22-producing T cells. These cytokines are also upregulated in AD and normalize with treatment, as recently shown for dupilumab-treated patients. We here asked for the role of slanMo in AD. Increased numbers of slanMo were found in AD skin lesions. In difference to other MPs in AD, slanMo lacked expression of FcɛRI, CD1a, CD14, and CD163. slanMo from blood of patients with AD expressed increased levels of CD86 and produced IL-12 and TNF-α at higher amounts than CD14+ monocytes and myeloid dendritic cells. While CD14+ monocytes from patients with AD revealed a reduced IL-12 production, we observed no difference in the cytokine production comparing slanMo in AD and healthy controls. Interestingly, experimentally induced mental stress, a common trigger of flares in patients with AD, rapidly mobilized slanMo which retained their high TNF-α-producing capacity. This study identifies slanMo as a distinct population of inflammatory cells in skin lesions and as proinflammatory blood cells in patients with AD. slanMo may, therefore, represent a potent future target for treatment of AD.

Current Concepts on 6-sulfo LacNAc Expressing Monocytes (slanMo)

“…Further, slanMo demonstrated a stronger programming of Th1 cells as compared to DC2 when cultured for 6 h before stimulation with LPS and then co-culture with cord blood T cells (26, 45). This is in line with the superior IL-12 production of slanMo when compared with DC2 after 6 h of spontaneous maturation (54). Another study assessed the Th17 programming capacity using allogenic naïve T cells.…”

“…Similar to psoriasis, a higher frequency of slanMo is also reported in the dermis of active skin lesions of AD patients. These slanMo lacked expression of FcεRI, CD1a, CD14, and CD163, thereby displaying a phenotype different from already described mononuclear phagocytes in AD patients (54). Peripheral blood slanMo of these patients retained their capacity to produce inflammatory cytokines and produced more TNF-α and IL-12 than myeloid DCs or classical monocytes after LPS or R848 stimulation (54).…”

“…They express a broad range of toll-like receptors (TLRs) but lack TLR3 and TLR9 (46). Stimulation of freshly isolated or immature slanMo with lipopolysaccharide (LPS) or CD40 ligand resulted in high-level TNF-α production (16, 26, 54). TNF-α-producing slanMo were identified in psoriasis, lupus skin lesions, glomerular capillaries of lupus nephritis, and tumor draining lymph nodes (30, 31, 43, 46).…”

“…Conditioning slanMo with IFN-γ for 6 h before stimulation with LPS or R848 increased (10-fold) their IL-12 secretion acknowledging the relevance of a positive feedback loop with IFN-γ producers such as Th1 cells and NK cells (55). slanMo revealed a strong response to TLR7 and TLR8 ligands with high IL-12 and IL-23 production (31, 54). Interestingly, IL-23 production required autocrine signaling by TNF-α and IL-1β (56, 57).…”

Neoadjuvant Radiochemotherapy Significantly Alters the Phenotype of Plasmacytoid Dendritic Cells and 6-Sulfo LacNAc+ Monocytes in Rectal Cancer

“…Tissue sections were boiled in citrate buffer (Zytomed Systems GmbH, Berlin, Germany) at pH 6.0 for 20 min for antigen retrieval. Subsequently, tissues were stained overnight at 4°C with either the polyclonal goat anti-BDCA-2 antibody (1:200, R&D Systems, Minneapolis, MN, USA) to evaluate pDCs (41) or the monoclonal mouse anti-slan antibody DD2 (1:10, Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany) to analyze slanMo (32, 34–36). Then, tissues used for pDC staining were incubated with a mouse anti-goat antibody solution (Thermo Fisher Scientific, Rockford, IL, USA) for 60 min.…”