Axl Receptor Blockade Protects from Invasive Pulmonary Aspergillosis in Mice

Abstract

Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment, which is quickly contained in the immunocompetent host but can cause lethal invasive aspergillosis in the immunocompromised host. We have recently demonstrated that Axl (one member of the Tyro3, Axl, Mertk receptor family) is a key regulator of antiviral immune responses in the lung. In this study, we investigated the role of Axl in antifungal immunity in a model of invasive pulmonary aspergillosis (IPA). In this model, Aspergillus fumigatus conidia were administered into the lungs of neutrophil-depleted mice, and the mice were monitored for survival, lung inflammatory response, and fungal clearance. The lethal effect of IPA was significantly reduced in anti-Axl mAb–treated mice compared with IgG control–treated mice. Targeting Axl significantly inhibited pulmonary inflammation, including the expression of IL-1β, IL-6, TNF-α, and chitinase-like proteins in whole lung. Further, anti-Axl mAb treatment significantly increased M1 macrophages that highly expressed inducible NO synthase and decreased M2 macrophages that expressed Arginase 1 and were found in inflammatory zone protein (Fizz1). More importantly, anti-Axl mAb treatment significantly increased the number of IFN-γ–producing T cells and NK cells compared with the IgG control group during IPA. Together, our results demonstrate that the Axl mAb treatment is protective during invasive aspergillosis in neutropenic mice. Collectively, these data suggest a potential deleterious role for Axl during primary immune responses directed against A. fumigatus and novel therapeutic strategy for IPA.

A critical role of Gas6/Axl signal in allergic airway responses during RSV vaccine‐enhanced disease

“…It is important that Gas6/Axl signaling dramatically enhances allergic immune responses during FI‐RSV VED, even though it simultaneously attenuates RSV‐F protein‐induced activation of DCs with the concomitant suppression of MHC II, CD40 and CD80 expression. Furthermore, Gas6/Axl also strongly suppresses IFN‐γ production in innate immune models 28 , 47 . These results seem to support the second hypothesis.…”

Deep sequencing of primary human lung epithelial cells challenged with H5N1 influenza virus reveals a proviral role for CEACAM1

“…H5N1 infection resulted in significant upregulation of a number of inflammatory cytokines/chemokines genes, including AXL and STING, which were significantly reduced by apocynin treatment to a level lower than that observed in uninfected cells (Table S4 ). It has been previously demonstrated that anti-AXL antibody treatment of PR8-infected mice significantly reduced lung inflammation and virus titers 40 . STING has been shown to be important for promoting anti-viral responses, as STING-knockout THP-1 cells produce less type I IFN following influenza A virus infection 41 .…”

Respiratory syncytial virus infection exacerbates pneumococcal pneumonia via Gas6/Axl-mediated macrophage polarization

“…Other possible mechanisms involved in the enhanced susceptibility to secondary bacterial infections include the attenuation of antibacterial protective immunity. In a previous study, we demonstrated that RSV stimulates the growth arrest-specific 6 (Gas6)/Axl axis, which regulates the anti-RSV and antifungal Th1 immune responses (16,17). Mechanistically, Axl, a high-affinity Gas6 receptor, was reported to attenuate the ability of dendritic cells (DCs) to respond to pathogen-associated molecular patterns through the DC-intrinsic Toll-like receptor (TLR) (18,19).…”