Tumor Necrosis Factor-α and IL-17A Activation Induces Pericyte-Mediated Basement Membrane Remodeling in Human Neutrophilic Dermatoses

Am J Pathol. 2017 Aug;187(8):1893-1906. doi: 10.1016/j.ajpath.2017.04.008. Epub 2017 Jun 10.

Abstract

Sweet syndrome (SS) is a prototypical neutrophilic dermatosis, a class of inflammatory diseases marked by elevated levels of tumor necrosis factor (TNF)-α and IL-17A, pathologic neutrophil recruitment, and microvascular remodeling. Histologic analyses of four matrix proteins-collagen I and IV, laminin, and fibronectin-in skin biopsies of patients with SS reveal that the basement membrane of dermal postcapillary venules undergoes changes in structure and composition. Increased neutrophil recruitment in vivo was associated with increases in collagen IV, decreases in laminin, and varied changes in fibronectin. In vitro studies using TNF-α and IL-17A were conducted to dissect basement membrane remodeling. Prolonged dual activation of cultured human pericytes with TNF-α and IL-17A augmented collagen IV production, similar to in vivo remodeling. Co-activation of pericytes with TNF-α and IL-17A also elevated fibronectin levels with little direct effect on laminin. However, the expression of fibronectin- and laminin-specific matrix metalloproteinases (MMPs), particularly MMP-3, was significantly up-regulated. Interactions between pericytes and neutrophils in culture yielded even higher levels of active MMPs, facilitating fibronectin and laminin degradation, and likely contributing to the varied levels of detectable fibronectin and the decreases in laminin observed in vivo. These data indicate that pericyte-neutrophil interactions play a role in mediating microvascular changes in SS and suggest that targeting MMP-3 may be effective in protecting vascular wall integrity.

MeSH terms

  • Aged
  • Basement Membrane / drug effects*
  • Basement Membrane / metabolism
  • Basement Membrane / pathology
  • Cells, Cultured
  • Collagen Type IV / metabolism
  • Female
  • Fibronectins / metabolism
  • Humans
  • Interleukin-17 / pharmacology*
  • Laminin / metabolism
  • Male
  • Matrix Metalloproteinase 3 / metabolism
  • Middle Aged
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Pericytes / drug effects*
  • Pericytes / metabolism
  • Pericytes / pathology
  • Sweet Syndrome / metabolism*
  • Sweet Syndrome / pathology
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Collagen Type IV
  • Fibronectins
  • Interleukin-17
  • Laminin
  • Tumor Necrosis Factor-alpha
  • Matrix Metalloproteinase 3