Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis

Abstract

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)–mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

Molecular Characteristics and Distribution of Adult Human Corneal Immune Cell Types

“…The KEGG pathway and GO annotation analyses were performed by using Metascape and showed that corneal DCs participate in cytokine signaling in the immune system and regulate leukocyte activation ( Figure 4C ). Surprisingly, we found that the corneal limbal DCs are mregDCs, which displayed high expressions of the markers LAMP3 and BIRC3 ( 24 ) ( Figure 4B and Supplementary Figure S2A ). This new subset of DCs has recently been identified in human skin mucosal tissues.…”

“…To better compare the mregDCs between the corneal limbus and the skin, we reanalyzed other publicly available skin datasets (GEO accession no. GSE176509) ( 24 ) and identified skin mregDCs using the same methods of t -SNE analysis and clustering. We found that, except for LAMP3 and BIRC3 , both corneal and skin mregDCs highly expressed CCR7 , CD74 , ID2 , GPR183 , CCL22 , IL4l1 , CD40 , and TXN ( Figure 4D and Supplementary Figure S2 ).…”

“…We found that, except for LAMP3 and BIRC3 , both corneal and skin mregDCs highly expressed CCR7 , CD74 , ID2 , GPR183 , CCL22 , IL4l1 , CD40 , and TXN ( Figure 4D and Supplementary Figure S2 ). In addition, corneal limbal mregDCs also expressed high levels of the pro-inflammatory cytokines IL1B, IL-15, and IL-23A, which are associated with mucosal inflammation ( 24 ). MregDCs have also been found to be involved in cytokine signaling and regulation of leukocyte activation ( Figures 2C and 4C, D ).…”

“…DCs displayed their ability to present antigens by highly expressing various HLA subtype genes such as HLA-DQA , HLA-DPA , and HLA-DPB . Recently, researchers have identified a small subset of skin DCs called mregDCs with high expressions of BIRC3 , LAMP3 , IL15 , CD40 , and CCR7 , and this subset has been thought to be associated with wound healing and the exacerbation of atopic dermatitis ( 24 , 37 , 38 ). It is surprising to find that corneal DCs also belong to mregDCs, with high expressions of the unique markers BIRC3 and LAMP3 .…”

Immunopathology and Immunotherapy of Inflammatory Skin Diseases

“…pSTAT3 and RORγt bind to IL17A and IL17F promoters and induce the expression of IL-17 ( 6 ). A recent study revealed that CD1c + CD14 + classical dendritic cell type 3 (cDC3) is the major source of IL-23 in psoriatic skin ( 11 ). Homodimers or heterodimers of IL-17A and IL-17F secreted by T cells primarily target keratinocytes in psoriatic skin, signaling through the IL-17RA-IL-17RC complex ( 12 ).…”