IFN-λ Diminishes the Severity of Viral Bronchiolitis in Neonatal Mice by Limiting NADPH Oxidase–Induced PAD4-Independent NETosis
| Autor: | Ismail Sebina, Ridwan B. Rashid, Md. Al Amin Sikder, Muhammed Mahfuzur Rahman, Tufael Ahmed, Daniel E. Radford-Smith, Sergei V. Kotenko, Geoffrey R. Hill, Tobias Bald, Simon Phipps |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 208:2806-2816 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Infants with attenuated type III IFN (IFN-λ) responses are at increased risk of severe lower respiratory tract infection (sLRI). The IL-28Rα–chain and IL-10Rβ–chain form a heterodimeric receptor complex, necessary for IFN-λ signaling. Therefore, to better understand the immunopathogenic mechanisms through which an IFN-λlo microenvironment predisposes to a sLRI, we inoculated neonatal wild-type and IL-28R–deficient (IL-28R−/−) mice with pneumonia virus of mice, a rodent-specific pneumovirus. Infected IL-28R−/− neonates displayed an early, pronounced, and persistent neutrophilia that was associated with enhanced reactive oxygen species (ROS) production, NETosis, and mucus hypersecretion. Targeted deletion of the IL-28R in neutrophils was sufficient to increase neutrophil activation, ROS production, NET formation, and mucus production in the airways. Inhibition of protein-arginine deiminase type 4 (PAD4), a regulator of NETosis, had no effect on myeloperoxidase expression, citrullinated histones, and the magnitude of the inflammatory response in the lungs of infected IL-28R−/− mice. In contrast, inhibition of ROS production decreased NET formation, cellular inflammation, and mucus hypersecretion. These data suggest that IFN-λ signaling in neutrophils dampens ROS-induced NETosis, limiting the magnitude of the inflammatory response and mucus production. Therapeutics that promote IFN-λ signaling may confer protection against sLRI. |
| Databáze: | OpenAIRE |
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