Involvement of fibrocytes in asthma and clinical implications

Abstract

Bloodborne fibrocytes are bone marrow-derived cells that participate in immune responses and exhibit pro-inflammatory and matrix remodelling properties. In patients with asthma receiving an adequate treatment, the blood fibrocyte count is very low and comparable to that obtained in healthy individuals. In these patients, a transient increase in fibrocyte numbers in the peripheral blood and in the airways occurs in concomitance with increased bronchial inflammation and reflects disease worsening and the need for more intensive treatment. Persistently elevated numbers of fibrocytes in the peripheral blood and in the bronchial mucosa are observed in chronically undertreated or corticosteroid-resistant asthma and are associated with persistent airway inflammation and ongoing remodelling of the bronchial wall. The asthmatic bronchial epithelium is the main source of fibrocyte chemoattractants in asthma and contributes with T helper type 2 lymphocytes and eosinophils to promote the proliferation and pro-remodelling function of recruited fibrocytes. The presence of elevated numbers of fibrocytes in the bronchial mucosa of allergic patients with undertreated or treatment-resistant asthma may also increase the risk of acute exacerbations because these cells can amplify T helper type 2 lymphocyte-driven inflammation on every exposure to the clinically relevant allergen and can promote further inflammation on rhinovirus infections by allowing viral replication and releasing additional pro-inflammatory factors. Improved methods for the isolation and functional analysis of pure populations of viable circulating fibrocytes have allowed a better understanding of the effector role of these cells. A reliable and clinically applicable assay has been developed to measure blood fibrocyte counts as outcome measure in future clinical trials. New therapeutic agents are needed to block both persistent inflammation and fibrocytosis in corticosteroid-resistant asthma.

Pathogenetic and prognostic roles of bloodborne fibrocytes in asthma

“…They circulate as a part of the peripheral blood mononuclear cell (PBMC) subpopulation of total leukocytes (Bucala et al, 1994;Chesney et al, 1998;Abe et al, 2001;Bianchetti et al, 2014) and have light scatter features on flow cytometry analysis similar to those of circulating myeloid dendritic cells (mDCs) and some myeloid progenitor cells (mPCs) (Bianchetti et al, 2014). They constitutively express some of the receptors that mediate the trafficking of other BMderived CD34 + PCs, mDCs, and eosinophils (Els) in asthma (Bellini et al, 2013;Mattoli, 2015), such as the C-X-C motif chemokine receptor 4 (CXCR4) (Abe et al, 2001), the C-C motif chemokine receptors (CCRs) CCR3, CCR5, and CCR7 (Abe et al, 2001;Isgrò et al, 2013a), and the receptor for interleukin (IL)-33 suppressor of tumorigenicity 2 (ST2) (Bianchetti et al, 2012a). Fcs have antigen-presenting function (Chesney et al, 1997;Isgrò et al, 2013b) and proinflammatory activities (Chesney et al, 1998;Bellini et al, 2012;Isgrò et al, 2013a;2013b) relevant to asthma (Mattoli, 2015).…”

“…They constitutively express some of the receptors that mediate the trafficking of other BMderived CD34 + PCs, mDCs, and eosinophils (Els) in asthma (Bellini et al, 2013;Mattoli, 2015), such as the C-X-C motif chemokine receptor 4 (CXCR4) (Abe et al, 2001), the C-C motif chemokine receptors (CCRs) CCR3, CCR5, and CCR7 (Abe et al, 2001;Isgrò et al, 2013a), and the receptor for interleukin (IL)-33 suppressor of tumorigenicity 2 (ST2) (Bianchetti et al, 2012a). Fcs have antigen-presenting function (Chesney et al, 1997;Isgrò et al, 2013b) and proinflammatory activities (Chesney et al, 1998;Bellini et al, 2012;Isgrò et al, 2013a;2013b) relevant to asthma (Mattoli, 2015). They participate in extracellular matrix (EM) remodeling through the production of some of the collagens and noncollagenous EM components synthesized in larger quantities by fibroblasts (Bucala et al, 1994;Chesney et al, 1998;Abe et al, 2001;Bianchetti et al, 2012b), and are also involved in collagen uptake and degradation (Bianchetti et al, 2012b).…”

“…As extensively discussed in a recent review (Mattoli, 2015), most of the studies that have evaluated the pathogenetic role of Fcs in asthma have adopted the method originally described by the group that discovered these cells (Bucala et al, 1994;Chesney et al, 1998) to identify Fcs in the peripheral blood and at tissue sites. Such method consists in the detection of cells coexpressing CD34 on the cell surface and type I collagen (COL1) in the cytoplasm by using specific antibodies and accurately distinguishes circulating Fcs from any other circulating cells, including the subpopulation of CD45…”

“…1). The recruitment of Fcs from the blood stream to the inflamed bronchial mucosa is largely mediated by chemokines and danger molecules produced by the bronchial epithelium (Bellini et al, 2013;Mattoli, 2015), particularly the CCR3/CCR5 ligands CCL5, CCL11 and CCL24, CXCL12, and IL-33 (Fig. 1).…”

“…1). ET-1 and transforming growth factor-β (TGF-β) are potent inducers of α-SMA expression in these cells, and the activation of signaling from TGF-β also strongly promotes the profibrotic function of Fcs infiltrating the bronchial mucosa by increasing their production of EM components and by inhibiting the uptake and degradation of collagenous proteins via the Endo180-mediated pathway (Mattoli, 2006;2015;Bellini et al, 2013) (Fig. 1).…”