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Because cholinergic urticaria is not a homogeneous disease, its subtype classification is essential for selection of the most suitable therapeutic method.

In secondary lymphoid organs, development and homeostasis of stromal cells such as podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) are regulated by hematopoietic cells, but the cellular and molecular mechanisms of such regulation have remained unclear. Here we show that ablation of either signal regulatory protein α (SIRPα), an Ig superfamily protein, or its ligand CD47 in conventional dendritic cells (cDCs) markedly reduced the number of CD4 cDCs as well as that of Pdpn FRCs and T cells in the adult mouse spleen. Such ablation also impaired the survival of FRCs as well as the production by CD4 cDCs of tumor necrosis factor receptor (TNFR) ligands, including TNF-α, which was shown to promote the proliferation and survival of Pdpn FRCs. CD4 cDCs thus regulate the steady-state homeostasis of FRCs in the adult spleen via the production of TNFR ligands, with the CD47-SIRPα interaction in cDCs likely being indispensable for such regulation.

Signal regulatory protein a (SIRPa), an immunoglobulin superfamily protein that is expressed predominantly in myeloid lineage cells such as dendritic cells (DCs) or macrophages, mediates cell-cell signaling. In the immune system, SIRPa is thought to be important for homeostasis of DCs, but it remains unclear whether SIRPa intrinsic to DCs is indeed indispensable for such functional role. Thus, we here generated the mice, in which SIRPa was specifically ablated in CD11c + DCs (Sirpa DDC ). Sirpa DDC mice manifested a marked reduction of CD4 + CD8a -conventional DCs (cDCs) in the secondary lymphoid organs, as well as of Langerhans cells in the epidermis. Such reduction of cDCs in Sirpa DDC mice was comparable to that apparent with the mice, in which SIRPa was systemically ablated. Expression of SIRPa in DCs was well correlated with that of either endothelial cell-selective adhesion molecule (ESAM) or Epstein-Barr virus-induced molecule 2 (EBI2), both of which were also implicated in the regulation of DC homeostasis. Indeed, ESAM + or EBI2 + cDCs were markedly reduced in the spleen of Sirpa DDC mice. Thus, our results suggest that SIRPa intrinsic to CD11c + DCs is essential for homeostasis of cDCs in the secondary lymphoid organs and skin.

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Objective-UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. Approach and Results-Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4 + forkhead box P3 + regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4 + forkhead box P3 + regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Conclusions-Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis. Correspondence to Naoto Sasaki, MD, PhD, Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan. E-mail n-sasaki@kobepharma-u.ac.jp; or Tomoya Yamashita, MD, PhD, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. E-mail tomoya@ med.kobe-u.ac.jp Despite advances in our understanding of the chronic immunoinflammatory nature of atherosclerosis, therapeutics aimed to intervene inflammation or immune system remains to be implemented in clinical practice. UVB-based phototherapy is the firstline treatment for immunoinflammatory cutaneous disorders such as psoriasis in humans without serious side effects. 15 Here, we investigated the effect of UVB irradiation on atherosclerosis and its underlying mechanisms in hypercholesterolemic mice. Our findings provide first evidence that UVB exposure inhibits the development and progression of atherosclerosis. Using hypercholesterolemic LC-depleted mice, we clearly demonstrated that epidermal LCs play a critical role in UVB-dependent induction of CD4 + UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses Foxp3+ Tregs, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Our data suggest that UVB-based modulation of the skin immune system for inducing atheroprotective Tregs may be an attractive approach to treat and prevent atherosclerosis. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results UVB Irradiation Inhibits the Initiation and Progression of Atherosclerotic Plaque Formation in Atherosclerotic MiceTo study the effect of UVB irradiation on the development of atherosclerosis, apolipoprotein E-deficient (Apoe −/− ) mice were irradiated with 2 or 5 kJ/m 2 UVB on...

UV radiation, particularly UVB, is the major risk factor for the induction of skin cancer, and it induces skin inflammation and immunosuppression. Although reports documented that Langerhans cells (LCs) play various roles in photobiology, little is known about whether they contribute to UVB-induced cutaneous inflammation. Recently, the anti-inflammatory effect of apoptotic cells was noted. This study focuses on the roles of LCs and apoptotic cells in UVB-induced cutaneous inflammation. We show that LCs are essential for resolution of UVB-induced cutaneous inflammation. Administration of quinolyl-valyl--methylaspartyl-[2,6-difluophenoxy]-methyl ketone, a broad-spectrum caspase inhibitor with potent antiapoptotic properties, inhibited the formation of UVB-induced apoptotic cells and aggravated UVB-induced cutaneous inflammation in wild-type mice. In contrast, exacerbation of UVB-induced cutaneous inflammation following quinolyl-valyl--methylaspartyl-[2,6-difluophenoxy]-methyl ketone administration was not observed in LC-depleted mice. These results suggest that the interaction between LCs and apoptotic cells is critical for resolution of UVB-induced cutaneous inflammation. Interestingly, UVB-induced apoptotic keratinocytes were increased in LC-depleted mice. In addition, we revealed that UVB-induced apoptotic keratinocytes were phagocytosed by LCs ex vivo and that prolongation of UVB-induced cutaneous inflammation following treatment with Cytochalasin D, an inhibitor of phagocytosis, was partially attenuated in LC-depleted mice. Collectively, our findings demonstrate that the interaction between LCs and apoptotic cells, possibly via LC-mediated phagocytosis of apoptotic keratinocytes, has an essential anti-inflammatory role in the resolution of UVB-induced cutaneous inflammation.