The chemokine CX3CL1/fractalkine regulates immunopathogenesis during fungal-associated allergic airway inflammation

Abstract

Individuals that present with difficult-to-control asthma and sensitivity to one or more fungal species are categorized as a subset of severe asthma patients belonging to a group herein referred to as severe asthma with fungal sensitization (SAFS). We have previously reported the identification of numerous cytokines and chemokines that were elevated in human asthmatics that were sensitized to fungi vs. non-fungal sensitized asthmatics. Here, we show that the unique chemokine CX3CL1 (fractalkine) is elevated in both bronchoalveolar lavage fluid and sputum from human asthmatics sensitized to fungi, implicating an association with CX3CL1 in fungal asthma severity. In an experimental model of fungal-associated allergic airway inflammation, we demonstrate that the absence of CX3CR1 signaling unexpectedly resulted in a profound impairment in lung function. Histological assessment of lung tissue revealed an unrestricted inflammatory response that was subsequently characterized by enhanced levels of neutrophils, eosinophils and inflammatory monocytes. Neutrophilic inflammation correlated with elevated IL-17A, proinflammatory cytokines (TNF-α, IL-1α IL-1β), neutrophil survival factors (G-CSF) and neutrophil-targeting chemokines (CCL3, CCL4). Eosinophilia correlated with elevated type 2 responses (IL-5, IL-13) whereas inflammatory monocyte levels correlated with elevated type 1 responses (IFN-γ, CXCL9) and survival factors (M-CSF). Despite enhanced inflammatory responses, the immunoregulatory cytokine IL-10 and the natural inhibitor of IL-1 signaling, IL-1RA, were significantly elevated rather than impaired. Regulatory T cell levels were unchanged, as were levels of the anti-inflammatory cytokines IL-35 and IL-38. Taken together, the CX3CL1/CX3CR1 axis preserves lung function during fungal-associated allergic airway inflammation through a non-classical immunoregulatory mechanism.

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

“…In contrast, we demonstrated that IL-1RA was an attractive and efficacious immunoprotective therapeutic for improving fungal asthma severity (21). Ongoing work in our laboratory has also identified CX3CL1 as an immunoprotective mediator during fungal asthma (26). YKL-40 has been implicated in non-type 2 asthma due to its relationship with mediators associated with IL-17-mediated inflammation (15,46).…”

Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma

“…37 Signaling by this chemokine receptor preserves lung function in fungal-induced allergic airway inflammation, which is mediated via a novel regulatory mechanism. 38 Our results…”

“…CX3CR1 is suppressed in circulating non‐classical monocytes from severe asthmatic patients 37 . Signaling by this chemokine receptor preserves lung function in fungal‐induced allergic airway inflammation, which is mediated via a novel regulatory mechanism 38 . Our results suggest an anti‐inflammatory role of this specific subtype, reversely linked to ambient PM 2.5 levels.…”

Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma

“…CX3CR1 is suppressed in circulating non-classical monocytes from severe asthmatic patients (29 ). Signaling by this chemokine receptor preserves lung function in fungal-induced allergic airway inflammation, which is mediated via a novel regulatory mechanism (30 ). Our results suggest an anti-inflammatory role of this specific subtype, reversely linked to ambient PM 2.5 level.…”