TY - JOUR
T1 - IFN-κ Diminishes the Severity of Viral Bronchiolitis in Neonatal Mice by Limiting NADPH Oxidase-Induced PAD4-Independent NETosis
AU - Sebina, Ismail
AU - Rashid, Ridwan B.
AU - Sikder, Md Al Amin
AU - Rahman, Muhammed Mahfuzur
AU - Ahmed, Tufael
AU - Radford-Smith, Daniel E.
AU - Kotenko, Sergei V.
AU - Hill, Geoffrey R.
AU - Bald, Tobias
AU - Phipps, Simon
N1 - Funding Information: This work was supported by National Health and Medical Research Council Project Grant 1141581 (to S.P.). Publisher Copyright: © 2022 by TheAmericanAssociation of Immunologists, Inc.
PY - 2022/6/15
Y1 - 2022/6/15
N2 - Infants with attenuated type III IFN (IFN-κ) 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-κ signaling. Therefore, to better understand the immunopathogenic mechanisms through which an IFN-κlo 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-28R2/2 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 proteinarginine 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-κ signaling in neutrophils dampens ROS-induced NETosis, limiting the magnitude of the inflammatory response and mucus production. Therapeutics that promote IFN-κ signaling may confer protection against sLRI.
AB - Infants with attenuated type III IFN (IFN-κ) 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-κ signaling. Therefore, to better understand the immunopathogenic mechanisms through which an IFN-κlo 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-28R2/2 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 proteinarginine 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-κ signaling in neutrophils dampens ROS-induced NETosis, limiting the magnitude of the inflammatory response and mucus production. Therapeutics that promote IFN-κ signaling may confer protection against sLRI.
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U2 - https://doi.org/10.4049/jimmunol.2100876
DO - https://doi.org/10.4049/jimmunol.2100876
M3 - Article
C2 - 35675958
SN - 0022-1767
VL - 208
SP - 2806
EP - 2816
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -