Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis

Cell Communication and Signaling

Review

Michiko Matsushita¹  Takashi Oka²  Katsuyoshi Takata²  Tadashi Yoshino²  Yasushi Horie³  Akira Morimoto⁴  Toshihiko Imamura⁵  Satoshi Kuwamoto⁶  Takeshi Iwasaki⁶  Keiko Nagata⁶  Ichiro Murakami⁶  Kazuhiko Hayashi⁶  Masako Kato⁶  Shinsaku Imashuku⁷  Jean Gogusev⁸  Francis Jaubert⁹ 

[1] Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University, 683-8503, Yonago, Japan;Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 700-8530, Okayama, Japan;Department of Pathology, Tottori University Hospital, 683-8503, Yonago, Japan;Department of Pediatrics, Jichi Medical University School of Medicine, 329-0498, Shimotsuke, Japan;Department of Pediatrics, Kyoto Prefectural University of Medicine, 602-8566, Kyoto, Japan;Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, 683-8503, Yonago, Japan;Division of Pediatrics and Hematology, Takasago-seibu Hospital, 676-0812, Takasago, Japan;Inserm U507 and U1016, Institut Cochin, 75014, Paris, France;University of Paris Descartes (Paris V), 75006, Paris, France;

关键词: Langerhans cell histiocytosis;    Merkel cell polyomavirus;    Interleukin 1;    Toll-like receptor;    Interleukin 17 receptor;    Src homology 2 domain tyrosine phosphatase 1;   

DOI  :  10.1186/s12964-015-0092-z

 received in 2014-12-09, accepted in 2015-02-10,  发布年份 2015

来源: Springer

【 摘 要 】

We propose Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV) infection triggers an interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including E-cadherin, matrix metalloproteinase, and Notch ligand induce LCH activity. We found that the tyrosine phosphatase SHP-1, which binds IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH). IL-1 stimulates T helper 17 cells and their signature cytokine IL-17 had been a matter of controversy. We detected higher levels of IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an IL-17 endocrine model that could settle the controversy. IL-1 is the first cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the IL-1 receptor, has functions in both RAS signaling and inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK–DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non–high-risk organs (0/12; P = .029). MCPyV infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and IL-1 loop regulation as potential therapeutic targets.

【 授权许可】

CC BY   
© Murakami et al.; licensee BioMed Central. 2015