Neutrophil Extracellular Traps Enhance Early Inflammatory Response in Sendai Virus-Induced Asthma Phenotype

Abstract

Paramyxoviral infection in childhood has been linked to a significant increased rate of asthma development. In mice, paramyxoviral infection with the mouse parainfluenza virus type I, Sendai virus (Sev), causes a limited bronchiolitis followed by persistent asthma traits. We have previously shown that the absence of cysteine protease dipeptidyl peptidase I (DPPI) dampened the acute lung inflammatory response and the subsequent asthma phenotype induced by Sev. Adoptive transfer of wild-type neutrophils into DPPI-deficient mice restored leukocyte influx, the acute cytokine response, and the subsequent mucous cell metaplasia that accompanied Sev-induced asthma phenotype. However, the exact mechanism by which DPPI-sufficient neutrophils promote asthma development following Sev infection is still unknown. We hypothesize that neutrophils recruited to the alveolar space following Sev infection elaborate neutrophil extracellular traps (NETs) that propagate the inflammatory cascade, culminating in the eventual asthma phenotype. Indeed, we found that Sev infection was associated with NET formation in the lung and release of cell-free DNA complexed to myeloperoxidase in the alveolar space and plasma that peaked on day 2 post infection. Absence of DPPI significantly attenuated Sev-induced NET formation in vivo and in vitro. Furthermore, concomitant administration of DNase 1, which dismantled NETs, or inhibition of peptidylarginine deiminase 4 (PAD4), an essential mediator of NET formation, suppressed the early inflammatory responses to Sev infection. Lastly, NETs primed bone marrow-derived cells to release cytokines that can amplify the inflammatory cascade.

NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma

“…However, an aberrant NETopathic response can be damaging to the host when excessive. This is consistent with murine studies demonstrating that viral-induced NET perturbance can elicit acute lung injury and airway inflammatory responses following challenges with influenza virus A and parainfluenza virus type I (Sendai virus) in experimental models of pneumonitis and asthma in vivo , respectively (27, 66).…”

Type I IFN exacerbates disease in tuberculosis-susceptible mice by inducing neutrophil-mediated lung inflammation and NETosis

“…We found that neutrophils were required for disease exacerbation induced in TB resistant C57Bl/6 mice by GM-CSF blockade during M. tuberculosis infection but additionally in TB-susceptible C3HeB/FeJ mice, and that neutrophil-driven disease exacerbation correlated with excessive NETosis at the site of infection in both models. NETs were originally described as a host antimicrobial defence mechanism against pathogens 41 , but recent studies reported that NETs can modulate immune responses and may also induce damaging inflammation in various infections and other inflammatory diseases 41 , 42 , 58 – 62 . NETs have been shown to be released in vitro by M. tuberculosis -infected mouse 63 and human 64 , 65 neutrophils, however, NETs did not prevent M. tuberculosis replication in vitro 63 .…”

Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis

“…The more severe organ damage seen in the infant septic mice is likely due to the elevated production of inflammatory cytokines in these organs that promotes the accumulation of neutrophils, which produce NET and other cytotoxic mediators. Moreover, NETs can activate macrophages and dendritic cells to produce inflammatory cytokines including IL-1β, TNF-α, and IL-6 [65], which, apart from mediating organ damage, can also recruit more neutrophils to the end organs.…”