TY - JOUR
T1 - Deficiency of melanoma differentiation-associated protein 5 results in exacerbated chronic postviral lung inflammation
AU - Kim, Won Keun
AU - Jain, Deepika
AU - Sánchez, Melissa D.
AU - Koziol-White, Cynthia J.
AU - Matthews, Krystal
AU - Ge, Moyar Q.
AU - Haczku, Angela
AU - Panettieri, Reynold A.
AU - Frieman, Matthew B.
AU - López, Carolina B.
PY - 2014/2/15
Y1 - 2014/2/15
N2 - Rationale: Respiratory viral infections can result in the establishment of chronic lung diseases. Understanding the early innate immune mechanisms that participate in the development of chronic postviral lung disease may reveal new targets for therapeutic intervention. The intracellular viral sensor protein melanoma differentiation-associated protein 5 (MDA5) sustains the acute immune response to Sendai virus, a mouse pathogen that causes chronic lung inflammation, but its role in the development of postviral chronic lung disease is unknown. Objectives: To establish the role of MDA5 in the development of chronic lung disease. Methods: MDA5-deficient or control mice were infected with Sendai virus. The acute inflammatory response was evaluated by profiling chemokine and cytokine expression and by characterizing the composition of the cellular infiltrate. The impact of MDA5 on chronic lung pathology and functionwas evaluated through histological studies, degree of oxygen saturation, and responsiveness to carbachol. Measurements and Main Results: MDA5 deficiency resulted in normal virus replication and in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced accumulation of alternatively activated macrophages. Diminished expression of neutrophil-recruiting chemokines was also observed in cells infected with influenza virus, suggesting a key role of MDA5 in driving the early accumulation of neutrophils at the infection site. The biased acute inflammatory response ofMDA5-deficientmice led to an enhanced chronic lung inflammation, epithelial cell hyperplasia, airway hyperreactivity, and diminished blood oxygen saturation. Conclusions: MDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung.
AB - Rationale: Respiratory viral infections can result in the establishment of chronic lung diseases. Understanding the early innate immune mechanisms that participate in the development of chronic postviral lung disease may reveal new targets for therapeutic intervention. The intracellular viral sensor protein melanoma differentiation-associated protein 5 (MDA5) sustains the acute immune response to Sendai virus, a mouse pathogen that causes chronic lung inflammation, but its role in the development of postviral chronic lung disease is unknown. Objectives: To establish the role of MDA5 in the development of chronic lung disease. Methods: MDA5-deficient or control mice were infected with Sendai virus. The acute inflammatory response was evaluated by profiling chemokine and cytokine expression and by characterizing the composition of the cellular infiltrate. The impact of MDA5 on chronic lung pathology and functionwas evaluated through histological studies, degree of oxygen saturation, and responsiveness to carbachol. Measurements and Main Results: MDA5 deficiency resulted in normal virus replication and in a distinct profile of chemokines and cytokines that associated with acute lung neutropenia and enhanced accumulation of alternatively activated macrophages. Diminished expression of neutrophil-recruiting chemokines was also observed in cells infected with influenza virus, suggesting a key role of MDA5 in driving the early accumulation of neutrophils at the infection site. The biased acute inflammatory response ofMDA5-deficientmice led to an enhanced chronic lung inflammation, epithelial cell hyperplasia, airway hyperreactivity, and diminished blood oxygen saturation. Conclusions: MDA5 modulates the development of chronic lung inflammation by regulating the early inflammatory response in the lung.
KW - Chronic lung disease
KW - Innate immunity
KW - Paramyxovirus
KW - Respiratory virus
UR - http://www.scopus.com/inward/record.url?scp=84894227444&partnerID=8YFLogxK
U2 - 10.1164/rccm.201307-1338OC
DO - 10.1164/rccm.201307-1338OC
M3 - Article
C2 - 24417465
AN - SCOPUS:84894227444
SN - 1073-449X
VL - 189
SP - 437
EP - 448
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 4
ER -