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

Abstract

Respiratory syncytial virus (RSV) is a common virus that causes lower respiratory infections across a wide range of ages. A licensed RSV vaccine is not available because vaccination with formalin-inactivated RSV (FI-RSV) and the subsequent RSV infection cause not only insufficient induction of neutralizing antibodies but also severe allergic airway responses, termed FI-RSV vaccine-enhanced disease (FI-RSV VED). However, the underlying mechanism has not been identified, although a Th2-biased immune response is known to be a hallmark of this disease. Our previous studies have shown that growth arrest-specific 6 (Gas6)/Axl signaling leads to Th2-biased immune responses during fungus-induced allergic airway inflammation. Here, we show that Gas6/Axl signaling also leads to FI-RSV VED and partially identify the mechanism in mice. Inhibiting Gas6/Axl signaling using Gas6-deficient mice, neutralizing antibodies, and a specific inhibitor of Axl attenuated allergic airway hyperresponsiveness, including airway inflammation, goblet cell hyperplasia, and Th2 cytokine production, in addition to increasing interferon-γ levels and the production of RSV-neutralizing IgG2a in FI-RSV VED. Gas6 was produced in lymph nodes during immunization with FI-RSV. Lymph node cells derived from immunized mice produced high levels of Gas6 and Th2 cytokines, but not IFN-γ, after restimulation with RSV. Finally, we found that dendritic cells stimulated with RSV-glycoprotein (G protein) produced Gas6 and that Axl signaling suppressed DC maturation and the induction of IL-12 production by the toll-like receptor 4 agonist RSV-fusion protein. Taken together, these results indicate that RSV-G protein-induced Gas6/Axl signaling causes allergic airway responses during FI-RSV VED.

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

“…The expression levels of Gas6 after infection are largely determined by the antigenic properties of individual pathogens. For RSV, G glycoprotein is reported to bind CX3CR1 (49), which initiates Gas6 production (50). Further studies are required for dissecting the mechanisms underlying infection-induced Gas6 production and immune cell polarization.…”

Multiple Regulatory Levels of Growth Arrest-Specific 6 in Mucosal Immunity Against an Oral Pathogen

“…Nevertheless, in both T cell types, the capability of the cells to secrete IFN-γ was significantly reduced due to the absence of GAS6 in DCs. A recent study has shown that AXL signaling downregulates IL-12 production by DCs ( 20 ), a cytokine required for generation of IFN-γ producing T cells ( 21 ). In addition, the AXL/GAS6 pathway was shown to diminish IFN-γ expression in NK cells as well as the expression of its master regulator, T-BET ( 22 ).…”

The role of phosphatidylserine on the membrane in immunity and blood coagulation

“…Some diseases and pathological processes may involve the binding of TAM to PtdSer. For example, AD [ 7 ], Tumor and cancer such as breast cancer [ 22 ], DENV [ 15 ], EBOV [ 10 – 12 ], and RSV [ 16 – 18 ] are involved.…”

“…As Immune and blood coagulation play a vital role in the human body and within them, PtdSer is essential for the normal execution of specific immune and coagulation processes. Once the functions of PtdSer are abnormal, they will cause many diseases, including Scott syndrome [ 3 ], Systemic lupus erythematosus (SLE) [ 4 ], Essential hypertension (EH) [ 5 ], Hemophilia A [ 6 ], Alzheimer’s disease (AD) [ 7 ], Human Immunodeficiency Virus (HIV) [ 8 ], Ebola virus (EBOV) [ 9 – 12 ], Dengue virus (DENV) [ 13 – 15 ] and Respiratory Syncytial Virus (RSV) [ 16 – 18 ], and certain tumors or cancers [ 19 – 22 ]. It was also speculated that PtdSer might be a potential mechanism or participant of inflammation and coagulation abnormalities in COVID-19 [ 23 , 24 ].…”