Repeated Exposure to Aspergillus fumigatus Conidia Results in CD4⁺T Cell-Dependent and -Independent Pulmonary Arterial Remodeling in a Mixed Th1/Th2/Th17 Microenvironment That Requires Interleukin-4 (IL-4) and IL-10

Abstract

Pulmonary arterial remodeling is a pathological process seen in a number of clinical disease states, driven by inflammatory cells and mediators in the remodeled artery microenvironment. In murine models, Th2 cell-mediated immune responses to inhaled antigens, such as purified Aspergillus allergen, have been reported to induce remodeling of pulmonary arteries. We have previously shown that repeated intranasal exposure of healthy C57BL/6 mice to viable, resting Aspergillus fumigatus conidia leads to the development of chronic pulmonary inflammation and the coevolution of Th1, Th2, and Th17 responses in the lungs. Our objective was to determine whether repeated intranasal exposure to Aspergillus conidia would induce pulmonary arterial remodeling in this mixed Th inflammatory microenvironment. Using weekly intranasal conidial challenges, mice developed robust pulmonary arterial remodeling after eight exposures (but not after two or four). The process was partially mediated by CD4 ؉ T cells and by interleukin-4 (IL-4) production, did not require eosinophils, and was independent of gamma interferon (IFN-␥) and IL-17. Furthermore, remodeling could occur even in the presence of strong Th1 and Th17 responses. Rather than serving an antiinflammatory function, IL-10 was required for the development of the Th2 response to A. fumigatus conidia. However, in contrast to previous studies of pulmonary arterial remodeling driven by the A. fumigatus allergen, viable conidia also stimulated pulmonary arterial remodeling in the absence of CD4 ؉ T cells. Remodeling was completely abrogated in IL-10 ؊/؊ mice, suggesting that a second, CD4 ؉ T cell-independent, IL-10-dependent pathway was also driving pulmonary arterial remodeling in response to repeated conidial exposure.

Interleukin-17 Drives Pulmonary Eosinophilia following Repeated Exposure to Aspergillus fumigatus Conidia

“…Increased T H 1, T H 2, T H 17, and T reg cells are present during peak inflammation (34). We have also found that IL-10 knockout mice have a defective T H 2 response to challenge with A. fumigatus conidia (56). Since IFN-␥ can also regulate the development of T H 17 cells (11), we examined whether IL-10, IFN-␥, or IL-4 play a role in regulating the development of T H 17 cells in the lungs of mice exposed to A. fumigatus conidia, using cytokine-specific knockout mice.…”

“…Similarly, there is a significant reduction in the percentage of CD4 ϩ CD25 ϩ FoxP3 ϩ T cells and a lower rate of CD4 T cell activation. We have previously shown that IL-10 Ϫ/Ϫ mice develop far less inflammation following four challenges than WT mice and do not develop pulmonary eosinophilia or T H 2 cells (56). It is therefore possible that IL-17 plays not only a direct role in promoting pulmonary eosinophilia and cellular accumulation during the allergic response but has a central, albeit subtle, role in shaping the initial immune response itself.…”

“…We have recently demonstrated that long-term repeated exposure to A. fumigatus conidia results in the development of progressive remodeling of small-to-medium-sized pulmonary arteries with concomitant luminal narrowing (56). The process was partially mediated by CD4 ϩ T cells and by IL-4 production, did not require eosinophils, and was independent of IFN-␥.…”

“…First, lung leukocytes were identified by CD45 expression. The following leukocyte subsets were then identified within this gate (56 (38).…”

Evolution of the Immune Response to Chronic Airway Colonization with Aspergillus fumigatus Hyphae

“…The importance of studying infection with live organisms is emphasized by the profile of the inflammatory response seen in mice colonized with Af beads, which differed from those challenged with conidia in suspension and from repeated challenge with conidia or other models that used sensitized mice (23,29). First, colonization with A. fumigatus hyphae resulted in only a modest Th2-type response early in infection.…”