Macrophage/epithelial cell CCL2 contributes to rhinovirus-induced hyperresponsiveness and inflammation in a mouse model of allergic airways disease

Abstract

Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1β, CCL7/MCP-3, CCL19/MIP-3β, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.

TNF-α and Macrophages Are Critical for Respiratory Syncytial Virus–Induced Exacerbations in a Mouse Model of Allergic Airways Disease

“…In our model, administration of anti-MCP-1 Abs completely suppressed AHR induction and reduced macrophage and eosinophil numbers in the airways. This is similar to the protective effect of MCP-1 neutralization on rhinovirus infectioninduced exacerbation of AHR mentioned previously (36). We also observed increased virus levels after anti-MCP-1 treatment (although not after 2-CA treatment), which highlights a role for MCP-1 in virus clearance.…”

“…Neutralizing MCP-1 suppresses AHR and immune cell infiltration during RSV-induced exacerbation MCP-1 has previously been reported to play important roles in the pathogenesis of asthma (36,52,53) and is increased in our model. Furthermore, increased MCP-1 levels potentially were downstream of TNF-a production.…”

“…Our group recently demonstrated that macrophages are a crucial link in the development of steroid-resistant airway inflammation and AHR via impaired glucocorticoid receptor translocation (30,33,34). In an acute rhinovirus-induced exacerbation model, induced MCP-1 increases AHR and airway inflammation in mice with allergic airways disease, with bronchoalveolar lavage fluid (BALF) macrophages being a major producer of MCP-1 (36). In an extension of these findings, rhinovirus-induced exacerbation also increased macrophages in the lung, which produced high levels of IL-13 (37).…”

CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection

“…Airway epithelial cells and macrophages produce CCL7, which may orchestrate cell recruitment in the context of oxidative stress (20,21). Induction of CCL7 during viral infections has been observed in asthmatic patients (22) and in models of RV infection dissecting the role of CCL2 (23). Our study significantly extends these findings by showing that CCL7 inhibition limited macrophage and neutrophil influx into the lung and the development of AHR in nonallergic mice, which was associated with suppression of the MAPK signaling factor ERK1 and NF-kB subunits p50 and p65.…”

Efeito do exercício físico na inflamação pulmonar e na resposta imunológica sistêmica em pacientes com asma persistente moderada ou grave

“…Níveis elevados de IL-6, IL-8 e MCP-1 têm sido observados tanto no escarro, quanto no plasma de pacientes asmáticos (Yokoyama et al, 1995;Shute et al, 1997;Daldegan et al, 2005;Wood et al, 2012) e estão negativamente associados com a função pulmonar e a hiperresponsividade brônquica (Dixon et al, 2008;Schneider et al, 2013;Morjaria et al, 2011;Grubek-Jaworska et al, 2012) e positivamente associados com inflamação das vias aéreas (Yokoyama et al, 1995;Wood et al, 2012).…”