Abstract
Respiratory virus infection, such as influenza, typically induces a robust type 1 (pro-inflammatory cytokine) immune response, however, the production of type 2 cytokines has been observed. Type 2 cytokine production during respiratory virus infection is linked to asthma exacerbation, however, type 2 cytokines may also be tissue protective. Interleukin (IL)-5 is a prototypical type 2 cytokine that is essential for eosinophil maturation and egress out of the bone marrow. However, little is known about the cellular source and underlying cellular and molecular basis for the regulation of IL-5 production during respiratory virus infection. We sought to identify the cellular source of IL-5 during influenza infection and determine the role of IL-5 during respiratory virus infection. Using a mouse model of influenza virus infection, we found a robust transient release of IL-5 into infected airways along with a significant and progressive accumulation of eosinophils in the lungs, particularly during the recovery phase of infection, i.e. following virus clearance. The cellular source of the IL-5 was group 2 innate lymphoid cells (ILC2) that infiltrated the infected lungs. Interestingly, the progressive accumulation of eosinophils following virus clearance was reflected in the rapid expansion of c-kit+ IL-5 producing ILC2. We further demonstrated that NKT cells, as well as alveolar macrophages (AM), were endogenous sources of IL-33 that enhance IL-5 production from ILC2. Importantly, the production of IL-5 was essential for optimal recovery from influenza as neutralization of IL-5 during the recovery phase resulted in delayed weight gain and impaired epithelial regeneration following virus clearance. This effect was independent of eosinophils and was instead, partially dependent on IL-5 acting through neutrophils expressing the IL-5 receptor. In the absence of IL-5 signaling, neutrophils exhibited heightened inflammatory activity and their depletion partially rescued the defect in recovery in IL-5 neutralized mice. Collectively, these results reveal that c-kit+ ILC2 interaction with IL-33 producing NKT and AM leads to abundant production of IL-5 by ILC2 and that IL-5 is essential for an optimal tissue repair response following influenza infection.
