The C-C motif chemokine ligands CCL5, CCL11, and CCL24 induce the migration of circulating fibrocytes from patients with severe asthma

Abstract

The C-C motif chemokine ligand 5 (CCL5), CCL11, and CCL24 are involved in the pathogenesis of asthma, and their function is mainly associated with the airway recruitment of eosinophils. This study tested their ability to induce the migration of circulating fibrocytes, which may contribute to the development of irreversible airflow obstruction in severe asthma. The sputum fluid phase (SFP) from patients with severe/treatment-refractory asthma (PwSA) contained elevated concentrations of CCL5, CCL11, and CCL24 in comparison with the SFP from patients with non-severe/treatment-responsive asthma (PwNSA). The circulating fibrocytes from PwSA expressed the receptors for these chemokines at increased levels and migrated in response to recombinant CCL5, CCL11, and CCL24. The SFP from PwSA induced the migration of autologous fibrocytes, and its activity was significantly attenuated by neutralization of endogenous CCL5, CCL11, and CCL24. These findings suggest that CCL5, CCL11, and CCL24 may contribute to the airway recruitment of fibrocytes in severe asthma.

Pathogenetic and prognostic roles of bloodborne fibrocytes in asthma

“…Fcs may instead play a major role in the recall phase of the allergic response, given that in allergic asthmatics every allergen exposure is associated with a progressive increase in the density of these cells in the bronchial mucosa from 4 to 24 h post allergen inhalation (Schmidt et al, 2003). In support of the ability of Fcs to amplify TH2L-driven inflammatory responses in the airways, a recent study from my laboratories has demonstrated that circulating Fcs and mDCs from allergic asthmatics similarly induce the proliferation of autologous circulating memory CD4 + THLs and the predominant release of the TH2 cytokines IL-4 and IL-5 from effector CD4 + THLs when pulsed with the clinically relevant allergen (Isgrò et al, 2013b).…”

“…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). These cells can exhibit predominant proinflammatory activities or predominant profibrotic properties at tissue sites, depending on the host's response to diverse environmental insults (allergens, viruses, irritants) (Isgrò et al, 2013b) and on the characteristics of the local cell infiltrate and cytokine milieu (Bellini et al, 2012;Sazuka et al, 2014). Similarly to other cells with combined antigenpresenting function and mesenchymal cell-like features (Muñoz-Fernández et al, 2006;Saada et al, 2006), they acquire a myofibroblast-like phenotype in vitro and at the tissue sites because of the expression of adhesion molecules also present on the surface of these cells (Bianchetti et al, 2012b) and the inducible synthesis of the intracellular contractile protein α-smooth muscle actin (α-SMA) (Abe et al, 2001;Schmidt et al, 2003;Mori et al, 2005;Saunders et al, 2009).…”

“…Fcs have an antigen-presenting function in vitro (Chesney et al, 1997;Isgrò et al, 2013b) and it has been reported (Chesney et al, 1997) that a small fraction of antigen-pulsed Fcs can localize to regional lymph nodes and prime naive T cells after intradermal injection in mice. However, the results of a study in a mouse model of allergic asthma do not support the ability of Fcs to induce immunological responses to allergens mediated by T helper type 2 lymphocytes (TH2Ls) (Schmidt et al, 2003).…”

“…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).…”

“…Its major limitation is that it precludes the isolation of a viable population of Fcs for functional analyses, because intracellular staining for COL1 requires prior cell fixation and permeabilization. To address this issue, novel multiple parameter approaches have been developed that allow for the identification and sorting of a pure population of circulating and tissue Fcs by flow cytometry on the basis of the coexpression at high levels on the cell surface of CD45/CD45RO, CD34, CD11b, and CD13 (Bianchetti et al, 2012a;Isgrò et al, 2013a;2013b), which is a distinctive feature of Fcs (Bucala et al, 1994;Chesney et al, 1998;Isgrò et al, 2013b;Bianchetti et al, 2014). Taking advantage of these technical improvements, it has been possible to uncover many functional properties of isolated Fcs and improve our understanding of the molecular mechanisms and signaling pathways involved in their trafficking and activation in asthma (Bellini et al, 2012;Bianchetti et al, 2012a;Isgrò et al, 2013a;2013b), as discussed below.…”