Immunological role of primary cilia of dendritic cells in human skin disease

Abstract

18Primary cilia are a unique organelle, known to provide a signaling hub for variety of cell 19 activities. Their potential role(s) in human immune homeostasis and diseases, however, have 20 yet to be explored. Here, we show that human dendritic cells (DCs) express primary cilia-like 21 structure. The primary cilia growth during DC proliferation by GM-CSF was shut off by DC 22 maturation agents, suggesting the role of primary cilia to transduce proliferation signaling. 23PDGFRα pathway, one of proliferation signal in primary cilia, promoted DC proliferation in a 24 dependent manner of intra-flagellar transport system. In epidermis with atopic dermatitis 25 patients, aberrant ciliated langerhans cells and keratinocytes with showing immature state 26 were observed that may play a potential role in inflammation and skin barrier disorder. 27

Primary Ciliary Signaling in the Skin—Contribution to Wound Healing and Scarring

“…Langerhans cells are bone-marrow-derived antigenpresenting immune cells located in the basal and suprabasal layer of the epidermis (Lombardi et al, 1993). Langerhans cells have characteristic features of dendritic cells, and the presence of PC in both Langerhans and dendritic cells has been shown (Toriyama et al, 2020). Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor that is mainly produced by immature Langerhans cells and stimulates the formation of PC in granulocytes and macrophages, activating the differentiation of granulocytes and macrophages from bone marrow precursor cells.…”

“…Granulocyte macrophage-colony stimulating factor (GM-CSF) is a hematopoietic growth factor that is mainly produced by immature Langerhans cells and stimulates the formation of PC in granulocytes and macrophages, activating the differentiation of granulocytes and macrophages from bone marrow precursor cells. Furthermore, PDGFRα localizes to PC, and PDGFα signaling promotes the proliferation of dendritic cells (Toriyama et al, 2020).…”

“…Interestingly, in the inflamed epidermis of atopic dermatitis patients, which has reduced barrier function, the number of cells with PC was increased, and atypically ciliated Langerhans cells and keratinocytes were found (Toriyama et al, 2020). As Langerhans cells present antigens to lymphocytes similar to macrophages, PC that regulate their activity are essential for the immune functions of the skin (Marks and Miller, 2013).…”

Primary Cilia in the Skin: Functions in Immunity and Therapeutic Potential

“…Thus, LCs play an important role in bridging innate immunity and acquired immunity. LCs are present at a rate of about 2–5% in normal epidermis but increase in AD: 13–16% of KCs isolated from AD patients in vitro , and nearly 30% in vivo , were positively stained with a proliferation marker, ki67 ( Czernielewski and Demarchez, 1987 ; Chorro et al, 2009 ; Toriyama et al, 2020 ). The elimination of LCs suppressed the immune response induced by protein antigens ( Nakajima et al, 2012 ).…”

“…It is very difficult to understand the pathophysiology of human inflammatory diseases because mechanisms of inflammatory responses are so complicated, and the immune response between model rodents and humans are usually different ( Beura et al, 2016 ). Recently, we showed that the primary cilium, which acts as a signaling hub, regulates the proliferation, differentiation, and maturation of human KCs and LCs ( Toriyama et al, 2020 ). This review discusses the function of primary cilia, especially inflammatory regulation, in human skin in the context of the literature, and the possible therapeutic potential of targeting signaling pathways transduced in primary cilia.…”