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.
Highlights
Respiratory viral illnesses are common in early life
neutrophil extracellular traps (NETs) have been shown to promote the resolution of neutrophilic inflammation in monosodium urate crystal-induced arthritis [26]
NETs are increasingly implicated in driving the pathogenesis of various diseases [11, 27,28,29,30,31]
Summary
Respiratory viral illnesses are common in early life. A majority of children with an initial episode of viral-induced bronchiolitis will have recurrent wheezing, prompting the association between viral infection, and subsequent development of asthma [1,2,3]. We have previously shown that the asthma phenotype was attenuated in the absence of dipeptidyl peptidase I (DPPI), a cysteine protease with many immunomodulatory activities [5]. This attenuation was accompanied by significant reduction in the number of alveolar neutrophils. Adoptive transfer of WT neutrophils into DPPI-deficient mice led to enhanced accumulation of DPPIdeficient neutrophils and inflammatory cytokine production in the alveolar space on day 4 post-infection (PI) and subsequent asthma phenotype development. The fact that DPPI-deficient neutrophils exhibited normal chemotaxis in response to various stimuli [5] but failed to accumulate at the site of inflammation (alveolar space) suggests a yet-to-be defined mechanism by which DPPI and DPPI-sufficient neutrophils modulate the early inflammatory responses to Sev
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
