Neuroinflammatory Mechanisms of Connective Tissue Fibrosis: Targeting Neurogenic and Mast Cell Contributions

Abstract

Significance: The pathogenesis of fibrogenic wound and connective tissue healing is complex and incompletely understood. Common observations across a vast array of human and animal models of fibroproliferative conditions suggest neuroinflammatory mechanisms are important upstream fibrogenic events. Recent Advances: As detailed in this review, mast cell hyperplasia is a common observation in fibrotic tissue. Recent investigations in human and preclinical models of hypertrophic wound healing and post-traumatic joint fibrosis provides evidence that fibrogenesis is governed by a maladaptive neuropeptide-mast cell-myofibroblast signaling pathway. Critical Issues: The blockade and manipulation of these factors is providing promising evidence that if timed correctly, the fibrogenic process can be appropriately regulated. Clinically, abnormal fibrogenic healing responses are not ubiquitous to all patients and the identification of those at-risk remains an area of priority. Future Directions: Ultimately, an integrated appreciation of the common pathobiology shared by many fibrogenic connective tissue conditions may provide a scientific framework to facilitate the development of novel antifibrotic prevention and treatment strategies.

Kevin A. Hildebrand MD, FRCSC

Figure 1.

Mast cells mediated inflammation and fibrosis. Mast cells circulate as CD34-positive precursor cells and terminally differentiate in connective tissues. Both IgE dependent and independent mechanisms can activate mast cells causing the release of preformed and newly synthesized pro-inflammatory mediators. Many of these mediators increase vascular permeability and promote the recruitment of other inflammatory cells and additional mast cell precursors. SCF is also secreted by activated fibroblasts and myofibroblasts, further potentiating mast cell recruitment and proliferation. TGF-β is a potent fibroblast mitogen and stimulator of myofibroblast differentiation. It also impedes myofibroblasts apoptosis. bFGF, basic fibroblast growth factor; CGRP, calcitonin gene-related peptide; CTGF, connective tissue growth factor; NGF, nerve growth factor; PDGF, platelet-derived growth factor; SCF, stem cell factor; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; VIP, vasoactive intestinal peptide. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

Photomicrographs of joint capsule tissue harvested from the posterior knee joint of New Zealand white rabbits with a post-traumatic joint contracture (A–D) and in rabbits treated with Ketotifen after joint injury (E–H). (I–L) A negative control (omission of primary antibodies) from a contracted joint capsule specimen. Nuclear DAPI staining illustrates cell densities in all three conditions (A, E, and I, respectively). Contracted joint capsules demonstrate high α-SMA, tryptase, and SP immunoreactivity indicative of myofibroblast, mast cell, and SP hyperplasia (white arrows, B, C, and D, respectively). In Ketotifen-treated animals, immunostaining for α-SMA, tryptase, and SP is markedly reduced. Endothelial staining is illustrated by the white block arrows (D and F). Immunoreactivity of α-SMA, tryptase, and SP is particularly enriched around microvascular elements, which is attributable to α-SMA expressed in pericytes and smooth muscle cells and the normal close anatomic relationship of mast cells (tryptase) and SP-expressing nerve fibers to the microvasculature. The images for each condition are of the same histological area viewed under different light sources and filters (original magnification 200×). α-SMA, alpha-smooth muscle actin; SP, substance P. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

Neuropeptide–mast cell–myofibroblast contributions to post-traumatic elbow fibrosis. Traumatic injury to the elbow initiates connective tissue repair processes mediated by mast cell signaling and myofibroblast differentiation. In at-risk patients, this pathway escapes normal regulatory control; excessive SP secretion from terminal nerve endings in the joint and periarticular connective tissue results in persistent mast cell stimulation, propagating the inflammatory cascade of myofibroblast-mediated connective tissue fibrosis. Over time, excessive collagen deposition results in permanent motion loss and joint dysfunction. Modified with permission from Monument et al. ECM, extracellular matrix. Adapted from figures 1 and 4 in Michael James Monument, David Hart, Andrew Dean Befus, Paul Salo, and Kevin Hildebrand, Posttraumatic elbow contractures: Targeting neuro-inflammatory fibrogenic mechanisms Journal of Orthopaedic Science 2013; 18(6): 869-877. Reprinted by permission. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound