Cigarette Smoke-Induced Pulmonary Inflammation Is TLR4/MyD88 and IL-1R1/MyD88 Signaling Dependent

Abstract

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-1β only in presence of ATP, whereas CSC alone promoted the TLR4/MyD88 signaling dependent production of IL-1α and pro-IL-1β 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.

Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice

“…48 Moreover, subacute (5 weeks) and chronic (26 weeks) CS exposure resulted in increased pulmonary expression of TLR4 in WT mice, and targeted disruption of TLR4 protected against acute and chronic CS-induced lung inflammatory response. 47,65 Therefore, the TLR4-NF-B signal pathway plays an important role in CS-mediated lung inflammatory response. Our findings corroborate with the above studies that acute and subchronic CS exposure led to increased levels of TLR4 mRNA and protein in the lungs of C57BL/6J mice.…”

Targeting Imbalance between IL-1β and IL-1 Receptor Antagonist Ameliorates Delayed Epithelium Wound Healing in Diabetic Mouse Corneas

“…The balanced production of IL-1b and its natural, specific inhibitor, sIL-1Ra, plays an important role in tissue homeostasis and in the susceptibility to and severity of many human diseases. 39,40 Wounding can initially induce IL-1b expression by endogenous danger signals or alarmins released from injured cells that can stimulate Toll-like receptors to induce IL-1b synthesis, 41,42 as well as epidermal growth factor receptor activation. 43 IL-1b, in turn, induces specifically the expressions of IL-1b and sIL-1Ra, as shown in cultured human endometrial stromal cells.…”

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

“…Protein samples pretreated with protease and phosphatase inhibitors were fractionated by SDS-PAGE, and upon electrophoresis, the proteins were transferred onto nitrocellulose membranes and blotted overnight as described previously (19). The anti-a-smooth muscle actin (a-SMA; ab5694; Abcam), anti-ERK1 (sc-93), anti-p-ERK1/2 (sc-16982R, Thr 202 /Tyr 204 ), anti-p38 (sc-728), anti-p-p38 (sc-7975R, Tyr 182 ), JNK (sc-571), anti-p-JNK1 (sc-6254), and anti-IL-17RA (ab134086) were used (Santa Cruz Biotechnology, Dallas, TX; Abcam; or Cell Signal Technology, Beverly, MA).…”