Caspase-1-Deficient Mice are More Susceptible Than Wild-Type Mice to Pneumonia Induced by Influenza A (H1N1)

Abstract

Although inflammasome-mediated caspase-1 activity and subsequent maturation of IL-1β are critical in host immune response against influenza, their roles in lung pathogenesis are not completely understood. Enhanced susceptibility of caspase-1-deficient mice to influenza has been attributed to decreased inflammation and augmented epithelial damage, while increased IL-1β release has been shown to exacerbate lung pathology. We challenged caspase-1-knockout and wild-type mice with high doses of influenza A (H1N1) virus (500 pfu). Only 10% mortality occurred in wild-type mice, in contrast to 40% mortality in caspase-1-knockout mice which exhibited severe pathologic manifestations as a result of overwhelming inflammatory and cytokine/chemokine responses. Infected caspase-1 knockout mice revealed neutrophil-dominant recruitment and elevated apoptotic inflammatory cells in the lungs, while 20% of these animals displayed focal lymphocytic infiltrates in the brains suggestive of mild focal encephalitis. In infected caspase-1 knockout mice, cytokine/chemokine levels were reduced at 3 days post-infection, but robust increase in the levels of TNF-α, IL-6, MIP-1α, MCP-1, MIP-1β and RANTES were observed at 6 days post-infection, coinciding with exaggerated neutrophil influx. These results support our previous findings implicating excessive neutrophil infiltration in pathologic complications during influenza pneumonia. In addition, we observed an induction of IL-1β release in caspase-1 knock-out mice at 6 days post-infection, indicating the involvement of caspase-1-independent activation of IL-1β. Microarray analyses of the lungs of infected caspase-1 knockout mice revealed upregulation of immune and inflammatory genes including CCL8, CCL4, IFN-γ, ICOS, PRF-1, KLRA4, KLRA7, KLRA18, NKG7, LTB4R and PTX3. Collectively, our data suggest that caspase-1-mediated effects are critical against severe influenza infection which can also trigger robust caspase-1-independent inflammatory responses, thus alluding to the complexity of innate immune regulation.

Keywords

caspase-1 influenza cytokines apoptosis pneumonia focal encephalitis

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