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. Chronic obstructive pulmonary disease (COPD)4is a major cause of morbidity among pulmonary diseases with high mortality (1). COPD is defined as a disease state characterized by poorly reversible chronic inflammatory response with progressive loss of lung function commonly as a result of cigarette smoking (2). In the bronchoalveolar lavage (BAL) fluid from COPD patients, an increase of proinflammatory cytokines and chemokines including TNF-α and IL-8 has been reported, and these mediators may play an important role in establishing and maintaining the inflammatory condition, characterized by high local neutrophilia (3). Cigarette smoke-induced chronic inflammation leads to the destruction of alveolar septae, and to the loss of surface area for gas exchange and to loss of elasticity known as emphysema (4). Cigarette smoke exposure rapidly induces production of reactive oxygen species impairing endothelial functions (5). The mechanisms leading to these changes after lung exposure to cigarette smoke are not completely understood. Emphysema may be due to a relative excess of cell-derived proteases, mainly serine proteases such as neutrophil elastase and matrix metalloproteinases (MMPs), that degrade the connective tissue of the lung, and to a relative paucity of antiproteolytic defenses (3). Among the MMPs, MMP-9 and MMP-12 produced by inflammatory cells or tissue cells seem to play a predominant role in the pathogenesis of emphysema. Indeed, increased concentrations of MMP-12 have been reported in the BAL fluid from COPD patients (6). In this study, using an acute model of cigarette smoke-induced inflammation in mice (7), we asked whether cigarette smoke components may be recognized by molecular pattern recognition receptors of the innate immune system such as TLRs, which sense not only microorganism associated molecular patterns but also environmental agents (8) or danger signals like heat shock proteins (hsp) (9, 10, 11, 12) or high mobility group box 1 protein (13, 14). The endotoxin that activates TLR4 is a component of pollution and smoke (15). Therefore, we addressed the role of TLR4 recognition and signaling in cigarette smoke-induced airway inflammation. Using mice deficient for TLR4, the adaptor protein MyD88 (16), or IL-1R1 (17), we report in this study for the first time that TLR4 is involved in the inflammatory response to cigarette smoke both in vitro and in vivo, and that MyD88/IL-1R1 signaling is central to this response.