Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis

Ichiro Murakami, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Masako Kato, Keiko Nagata, Yasushi Horie, Kazuhiko Hayashi, Toshihiko Imamura, Akira Morimoto, Shinsaku Imashuku, Jean Gogusev, Francis Jaubert, Katsuyoshi Takata, Takashi Oka, Tadashi Yoshino

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)13
Number of pages1
JournalCell Communication and Signaling
Volume13
DOIs
Publication statusPublished - 2015

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Langerhans Cell Histiocytosis
Interleukin-1
Genes
Dual Specificity Phosphatase 6
Interleukin-17
Extracellular Signal-Regulated MAP Kinases
Fibrosarcoma
Merkel cell polyomavirus
Langerhans Cells
Interleukin-1 Receptor-Associated Kinases
Non-Receptor Type 6 Protein Tyrosine Phosphatase
Cells
Tissue
Cytokines
Polyomavirus Infections
Mutation
Phosphorylation
Interleukin-1 Receptors
T-cells
Cadherins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis. / Murakami, Ichiro; Matsushita, Michiko; Iwasaki, Takeshi; Kuwamoto, Satoshi; Kato, Masako; Nagata, Keiko; Horie, Yasushi; Hayashi, Kazuhiko; Imamura, Toshihiko; Morimoto, Akira; Imashuku, Shinsaku; Gogusev, Jean; Jaubert, Francis; Takata, Katsuyoshi; Oka, Takashi; Yoshino, Tadashi.

In: Cell Communication and Signaling, Vol. 13, 2015, p. 13.

Research output: Contribution to journalArticle

Murakami, I, Matsushita, M, Iwasaki, T, Kuwamoto, S, Kato, M, Nagata, K, Horie, Y, Hayashi, K, Imamura, T, Morimoto, A, Imashuku, S, Gogusev, J, Jaubert, F, Takata, K, Oka, T & Yoshino, T 2015, 'Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis', Cell Communication and Signaling, vol. 13, pp. 13. https://doi.org/10.1186/s12964-015-0092-z
Murakami, Ichiro ; Matsushita, Michiko ; Iwasaki, Takeshi ; Kuwamoto, Satoshi ; Kato, Masako ; Nagata, Keiko ; Horie, Yasushi ; Hayashi, Kazuhiko ; Imamura, Toshihiko ; Morimoto, Akira ; Imashuku, Shinsaku ; Gogusev, Jean ; Jaubert, Francis ; Takata, Katsuyoshi ; Oka, Takashi ; Yoshino, Tadashi. / Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis. In: Cell Communication and Signaling. 2015 ; Vol. 13. pp. 13.
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AU - Murakami, Ichiro

AU - Matsushita, Michiko

AU - Iwasaki, Takeshi

AU - Kuwamoto, Satoshi

AU - Kato, Masako

AU - Nagata, Keiko

AU - Horie, Yasushi

AU - Hayashi, Kazuhiko

AU - Imamura, Toshihiko

AU - Morimoto, Akira

AU - Imashuku, Shinsaku

AU - Gogusev, Jean

AU - Jaubert, Francis

AU - Takata, Katsuyoshi

AU - Oka, Takashi

AU - Yoshino, Tadashi

PY - 2015

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N2 - 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.

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