IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection

Abstract

Influenza infection primarily targets the upper respiratory system, leading to a severe destruction of the epithelial cell layer. The role of immune cells in the regeneration of tracheal and bronchial epithelial cells is not well defined. Here, we investigated the production of pro-constructive cytokine, Interleukin-22 (IL-22), in the bronchoalveolar lavage (BAL), trachea, lung tissue, and spleen during influenza infection. We found that conventional NK cells (NCR1+NK1.1+CD127−RORγt−) were the predominant IL-22-producers in the BAL, trachea and lung tissues. Tracheal epithelial cells constitutively expressed high levels of IL-22R and underwent active proliferation in response to IL-22 in the wild type (WT) mice. Infection of IL-22−/− mice with influenza virus resulted in a severe impairment in the regeneration of tracheal epithelial cells. In addition, IL-22−/− mice continued to lose body weight even after 10 days post infection (DPI 10) without any recovery. Tracheal epithelial cell proliferation was significantly reduced in IL-22−/− mice during influenza infection. Adoptive transfer of IL-22 sufficient but not IL-22 deficient NK cells into IL-22−/− mice restored the tracheal/bronchial epithelial cell regeneration and conferred protection against inflammation. Our findings strongly suggest that conventional NK cells have evolved to both kill virus-infected cells and also to provide vital cytokines for tissue regeneration.

Chlorine gas exposure increases susceptibility to invasive lung fungal infection

“…Collectively, the lack of robust IL-17A and IL-22 production in the lungs of Cl 2 -exposed mice after microbial challenge suggests that a component of Cl 2 -induced immunosuppression is lower induction of soluble antimicrobial factors via the IL-17A and IL-22 axis. Since IL-17A and IL-22 are essential effector cytokines that coordinate the immune response to multiple lung pathogens, including A. fumigatus (26,61), influenza (33,46), Pseudomonas aeruginosa (15), Klebsiella pneumonia (4), and Staphylococcus aureus (17,32), our finding has broad implications for lung host defense mechanisms impaired by Cl 2 gas exposure (and potentially other agents that target the respiratory tract).…”

“…The inflammatory cytokines IL-17A and IL-22 are essential for host defense against multiple viral and bacterial lung pathogens (4,5,21,33). A major function of IL-17A and IL-22 in the lung is the induction of epithelial antimicrobial responses (4).…”

Helper T-Cell Type 17 Cytokines and Immunity in the Lung

“…IL-22 has also been shown in a model of ventilator-induced lung injury to have potential therapeutic benefit (37). It has been shown that the lack of IL-22 is associated with reduced epithelial repair (38) and increased fibrosis (36) in experimental influenza infection. IL-22 can activate STAT3 in airway epithelium and thus can augment the expression of antimicrobial genes as well as aid in epithelial repair (39).…”

Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection

“…However, there are also examples in which NK cells exacerbate morbidity and pathology during lethal dose influenza virus infection in mice (24,25), which indicate that NK cells may play dual roles during influenza virus infection in mice, conferring beneficial or deleterious function depending on the viral dose. Furthermore, production of IL-22 by NK and NKT cells has an important role in the repair of epithelial damage caused by IAV (26,27). Meanwhile, NK cells play important roles in bridging the innate and adaptive immune responses to IAV (28).…”