Cytokine and chemokine responses following pulmonary challenge with Aspergillus fumigatus: obligatory role of TNF-α and GM-CSF in neutrophil recruitment

Abstract

Aspergillus fumigatus causes life-threatening invasive pulmonary aspergillosis in the immunocompromised patient. In this study we have used a murine model of intratracheal challenge with A. fumigatus to investigate the recruitment of inflammatory cells in the lung and the expression of proinflammatory cytokines and chemokines. Our results show that A. fumigatus causes an acute pulmonary inflammatory response which is dominated by neutrophils and to a lesser extent macrophages. During the peak of infection, proinflammatory cytokines (TNF-alpha, GM-CSF and IL-1beta) and chemokines (MIP-1alpha, MCP-1 and MIP-2), are induced within the lung. Furthermore, treatment of mice with neutralizing anti-TNF-alpha and anti-GM-CSF mAbs reduced the influx of neutrophils into the lung and delayed fungal clearance. Our observations show that Aspergillus conidia are effective inducers of host chemokine responses both in vitro and in vivo. Furthermore, TNF-alpha and GM-CSF play a central role in the recruitment of neutrophils into the lung in response to this clinically important pathogen.

Pulmonary immune responses induced in BALB/c mice by Paracoccidioides brasiliensis conidia

“…At 48 h post-challenge, they found an increase in the number of total cells, mainly due to PMN leukocytes influx in the BAL fluid. These results are consistent with other experimental models using medical important fungi such as Candida albicans, Aspergillus fumigatus and Pneumocystis carinii [56][57][58][59], where it has been demonstrated that the recruitment of PMNs occurs during first day post-challenge, and that this recruitment is mediated by pro-inflammatory cytokines including TNF-a, IL-6, IL-1b and granulocyte-macrophage colony stimulating factor (GM-CSF). As described below, in this model of pulmonary PCM, Fig.…”

T Cell Vaccination in Mice with Invasive Pulmonary Aspergillosis

“…A recent study indicated that TNF-␣ and chemokines orchestrate the lung inflammatory response to IPA (31,32), so that in vivo depletion of TNF-␣ resulted in a reduction in lung neutrophil infiltration and a reduced production of C-X-C and especially C-C chemokines. It is conceivable that the same mediators are at work in the recruitment of neutrophils in response to Aspergillus Ags.…”

Macrophage Inflammatory Protein-1α Is a Critical Mediator of Host Defense Against Invasive Pulmonary Aspergillosis in Neutropenic Hosts

“…In animal models of infections, MIP-1␣ has been shown to play a critical role in the cellular recruitment and inflammatory response to coxsackie and influenza infections (34), endotoxemia (35), bacterial pneumonia (36), and cryptococcosis (37,38). Two previous studies have examined the expression of MIP-1␣ in response to Aspergillus species; one showed that rat alveolar macrophages express MIP-1␣ mRNA when exposed to A. fumigatus conidia in vitro (39), and another demonstrated that MIP-1␣ is induced in the lungs after intrapulmonary challenge with conidia (40). We have previously shown that neutralization of TNF in experimental pulmonary aspergillosis results in increased mortality and decreased fungal clearance, which was associated with decreased levels of lung MIP-1␣ (41).…”