Hypothetical Atopic Dermatitis-Myeloproliferative Neoplasm Syndrome

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease. Myeloproliferative neoplasms (MPNs) are hematopoietic malignancies caused by uncontrolled proliferation of hematopoietic stem/progenitor cells. Recent studies have described several mutant mice exhibiting both AD-like skin inflammation and MPN. Common pathways for skin inflammation encompass overexpression of thymic stromal lymphopoietin and reduced signaling of epidermal growth factor receptor in the epidermis, while overproduction of granulocyte-colony-stimulating factor by keratinocytes and constitutive activation of Stat5 in hematopoietic stem cells are important for the development of MPN. The murine studies suggest the existence of a similar human disease tentatively termed as the atopic dermatitis-myeloproliferative neoplasm syndrome.

Keywords: atopic dermatitis; hematopoietic stem cell; mast cell; mouse models; myeloproliferative neoplasm.

Figure 1

Pathogenic mechanisms for the hypothetical AD-MPN syndrome. Keratinocyte-derived TSLP (and impaired skin barrier) seems to play a critical role in dendritic cell-dependent Th2 responses to offending allergens or injury. Th2 cytokines predominantly cause an acute inflammation and activation of several types of cells, including dermal fibroblasts. Th2 cytokine-stimulated fibroblasts secrete periostin, an α_v integrin-interacting matricellular protein, which in turn stimulates keratinocytes to secrete TSLP (35). TSLP also stimulates mast cells to secrete Th2 and other cytokines. Periostin secretion from dermal fibroblasts depends on Th2 cytokines and mast cells, forming at least two positive feedback loops (indicated thick and thin circular loops). Keratinocyte-derived G-CSF is important for MPN development in certain mutant mice. Expression of genes coding for G-CSF and TSLP is under control of c-Fos/AP-1, which is positively regulated by EGFR and negatively regulated by Notch signaling and JunB. The proliferative and survival properties of hematopoietic stem cells (HSCs) are positively regulated by Stat5, whose constitutive activation can lead to MPN. PLC-β3 negatively regulates TSLP production in keratinocytes, periostin production in fibroblasts, and Stat5 activity in HSCs, mast cells, and Th2 cells. DC, dendritic cell; NICD, Notch intracellular domain; RBPj, recombination signal binding protein for immunoglobulin kappa region.