Cigarette smoke-induced pulmonary inflammation is TLR4/MyD88 and IL-1R1/MyD88 signaling dependent.
Acute cigarette smoke exposure of the airways (two cigarettes twice daily for three days) induces acute inflammation in mice. In this study, we show that airway inflammation is dependent on Toll-like receptor 4 and IL-1R1 signaling. Cigarette smoke induced a significant recruitment of neutrophils in the bronchoalveolar space and pulmonary parenchyma, which was reduced in TLR4-, MyD88-, and IL-1R1-deficient mice. Diminished neutrophil influx was associated with reduced IL-1, IL-6, and keratinocyte-derived chemokine levels and matrix metalloproteinase-9 activity in the bronchoalveolar space. Further, cigarette smoke condensate (CSC) induced a macrophage proinflammatory response in vitro, which was dependent on MyD88, IL-1R1, and TLR4 signaling, but not attributable to LPS. Heat shock protein 70, a known TLR4 agonist, was induced in the airways upon smoke exposure, which probably activates the innate immune system via TLR4/MyD88, resulting in airway inflammation. CSC-activated macrophages released mature IL-1beta only in presence of ATP, whereas CSC alone promoted the TLR4/MyD88 signaling dependent production of IL-1alpha and pro-IL-1beta implicating cooperation between TLRs and the inflammasome. In conclusion, acute cigarette exposure results in LPS-independent TLR4 activation, leading to IL-1 production and IL-1R1 signaling, which is crucial for cigarette smoke induced inflammation leading to chronic obstructive pulmonary disease with emphysema.
Doz
Emilie
E
University of Orleans and Centre National de la Recherche Scientifique UMR6218, Molecular Immunology and Embryology, France.
Noulin
Nicolas
N
Boichot
Elisabeth
E
Guénon
Isabelle
I
Fick
Lizette
L
Le Bert
Marc
M
Lagente
Vincent
V
Ryffel
Bernhard
B
Schnyder
Bruno
B
Quesniaux
Valérie F J
VF
Couillin
Isabelle
I
D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced* / Q000235:genetics* / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D012906:Smoke; D014026:Nicotiana / Q000633:toxicity*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
D018840:HSP70 Heat-Shock Proteins; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; D012906:Smoke; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020780:Matrix Metalloproteinase 9