Long-term activation of TLR3 by poly(I:C) induces inflammation and impairs lung function in mice.
BACKGROUND
The immune mechanisms associated with infection-induced disease exacerbations in asthma and COPD are not fully understood. Toll-like receptor (TLR) 3 has an important role in recognition of double-stranded viral RNA, which leads to the production of various inflammatory mediators. Thus, an understanding of TLR3 activation should provide insight into the mechanisms underlying virus-induced exacerbations of pulmonary diseases.


METHODS
TLR3 knock-out (KO) mice and C57B6 (WT) mice were intranasally administered repeated doses of the synthetic double stranded RNA analog poly(I:C).


RESULTS
There was a significant increase in total cells, especially neutrophils, in BALF samples from poly(I:C)-treated mice. In addition, IL-6, CXCL10, JE, KC, mGCSF, CCL3, CCL5, and TNFalpha were up regulated. Histological analyses of the lungs revealed a cellular infiltrate in the interstitium and epithelial cell hypertrophy in small bronchioles. Associated with the pro-inflammatory effects of poly(I:C), the mice exhibited significant impairment of lung function both at baseline and in response to methacholine challenge as measured by whole body plethysmography and an invasive measure of airway resistance. Importantly, TLR3 KO mice were protected from poly(I:C)-induced changes in lung function at baseline, which correlated with milder inflammation in the lung, and significantly reduced epithelial cell hypertrophy.


CONCLUSIONS
These findings demonstrate that TLR3 activation by poly(I:C) modulates the local inflammatory response in the lung and suggest a critical role of TLR3 activation in driving lung function impairment. Thus, TLR3 activation may be one mechanism through which viral infections contribute toward exacerbation of respiratory disease.
Stowell
Nicole C
NC
Discovery Research, Centocor Research & Development, Inc, Radnor, Pennsylvania, USA. nstowell@cntus.jnj.com
Seideman
Jonathan
J
Raymond
Holly A
HA
Smalley
Karen A
KA
Lamb
Roberta J
RJ
Egenolf
Devon D
DD
Bugelski
Peter J
PJ
Murray
Lynne A
LA
Marsters
Paul A
PA
Bunting
Rachel A
RA
Flavell
Richard A
RA
Alexopoulou
Lena
L
San Mateo
Lani R
LR
Griswold
Don E
DE
Sarisky
Robert T
RT
Mbow
M Lamine
ML
Das
Anuk M
AM
D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010991:Plethysmography; D011070:Poly I-C / Q000494:pharmacology*; D012129:Respiratory Function Tests; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D016207:Cytokines; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D011070:Poly I-C