Eosinophil Activation of Fibroblasts from Chronic Allergen-Induced Disease Utilizes Stem Cell Factor for Phenotypic Changes

Abstract

In the present studies the role of stem cell factor (SCF) in mediating eosinophil and fibroblast activation during their interaction was investigated. SCF was significantly higher in fibroblasts grown from lungs of chronic allergen-challenged mice compared to fibroblasts grown from normal mice. When eosinophils were layered onto fibroblasts from allergic mice, a significant increase in SCF was detected compared to fibroblasts from nonallergic mice. The interaction of fibroblasts with eosinophils also increased the production of asthmaassociated chemokines, CCL5 and CCL6, was dependent on cell-to-cell interaction, and was observed only with fibroblasts derived from lungs of chronic allergen-challenged mice and not from those derived from unchallenged normal mice. Chemokine production was significantly decreased when anti-SCF antibodies were added during eosinophil-fibroblast interaction. The interaction of fibroblasts from chronic allergen-challenged mice with eosinophils also increased ␣-smooth muscle cell actin and procollagen I expression as well as induced transforming growth factor-␤. The changes in myofibroblast activation were dependent on SCF-mediated pathways because anti-SCF antibody treatment reduced the expression of all three of these latter fibrosisassociated markers. Thus , our data suggest that SCF mediates an important activation pathway for fibroblasts during chronic allergic responses on interaction with recruited eosinophils and suggest a potential mechanism of airway remodeling during chronic disease. Allergic airway inflammation is characterized by peribronchial eosinophil accumulation accompanied by mucus production and airway changes. Structural changes in the asthmatic airway include an increase in smooth muscle mass and deposition of extracellular matrix proteins. These changes correlate with airway hyperresponsiveness, reduced lung function, and an increase in fibroblast and myofibroblast numbers. These debilitating effects are not specifically targeted by current therapeutic agents, presenting a clinical challenge that might be better addressed by an enhanced understanding of the mechanisms. 1 In addition to contributing to airway remodeling, lung fibroblasts may also play a role in local regulation of immune and inflammatory responses. Fibroblasts are a potential source of granulocyte monocyte-colony stimulating factor (GM-CSF) and stem cell factor (SCF), known to promote differentiation, activation, and survival of eosinophils and mast cells. 2 Eosinophils have been shown to highly express c-kit (SCF receptor) on their surface. 3,4 We have previously shown that SCF is an important eosinophil-activating factor 4 that influences eosinophil recruitment in allergic airway inflammation. 5 SCF-induced activation of eosinophils has been shown to up-regulate expression of fibroblast growth factors, such as FGF5 and FGF7 (KGF). 4 Eosinophils also express at least two potent mediators [interleukin (IL)-1␤ and transforming growth factor (TGF)-␤] that induce a myofibroblast phenotype. The emergi...

Effect of roflumilast on airway remodelling in a murine model of chronic asthma

“…Our previous works with nilotinib and imatinib, which is a potent inhibitor of c-Kit and platelet-derived growth factor receptor, also reduced airway remodelling in murine asthma model [25,39]. Anti-SCF antibody treatment reduced the expression of fibrosis associated markers, such as TGF-b [45]. From our results, roflumilast treatment led to lower lung fibroblast proliferation induced by SCF.…”

“…Blockade of SCF expression suppressed Th2 cytokines in several other studies [25,37,[41][42][43][44]. Anti-SCF antibody treatment reduced the expression of fibrosis associated markers, such as TGF-b [45]. In addition, SCF, Th2 cytokines, and TGF-b1 were all significantly reduced with imatinib in our prior study [25].…”

Group 2 innate lymphoid cells (ILC2) are regulated by stem cell factor during chronic asthmatic disease

“…The α-SCF248 Mab treatment mediated a reduction in the expression of these genes in whole lung mRNA compared to control treated allergic animals (Figure 5A). To specifically examine the fibroblast phenotype, lungs from animals chronically challenged with allergen were dispersed, and fibroblasts were grown from them as previously described 25 . Separate fibroblasts lines were developed from each mouse and the analysis was performed after a single passage in vitro when >95% of the cells were fibroblasts (not shown).…”

Absence of α4 but not β2 integrins restrains development of chronic allergic asthma using mouse genetic models

“…Interaction of fibroblasts with eosinophils that leads to increased production of cytokines is mediated through SCF [37]. Because of the known influence of SCF on integrin activation [38] and expression of SCF and c-kit in human asthmatic airways [39], it could be speculated that SCF effects are at least partially integrin-dependent, as both c-kit and α4 integrin signaling are linked to the same pathways that regulate migration and activation of mast cells [40].…”