According to World Health Organization estimates, 80 million people have moderate to severe chronic obstructive pulmonary disease 
. Although emphasis has been placed on reducing smoking prevalence, a greater understanding of the mechanisms that contribute to COPD pathogenesis and exacerbation of the stable disease are equally relevant given the burden this disease places on health care systems, and the addictive nature and chronic persistence of the cigarette smoking habit. Moreover, the efficacy of many existing anti-inflammatory interventions have been disappointing (reviewed in 
), necessitating the design of novel therapeutics. Given that IL-1 family members play a central role in innate immune responses and in many pathogenic inflammatory disorders, we assessed in humans and mice the role of IL-1α and β, and their cognate receptor, IL-1R1, play in promoting cigarette smoked-induced inflammation.
In this study, we report the presence of both IL-1α and β in COPD patients. While previous studies have highlighted a role for IL-1β in disease progression 
, we observed a strong correlation between IL-1α and IL-1β levels in sputum obtained from COPD patients in stable disease and during episodes of acute exacerbation. Mechanistically, we demonstrate using blocking antibodies and gene-deficient mice that cigarette smoke-induced neutrophilia, as well as, expression of the neutrophil recruiting chemokines CXCL -1, -2, and -5 was IL-1α dependent, but independent of IL-1β. IL-1α antibody intervention also attenuated expression of GM-CSF and MMP-12, two molecules that have been implicated in cigarette smoke-induced inflammation and tissue damage 
. Our data therefore suggest a novel role for IL-1α in the pathogenesis of COPD.
Recently, macrophages have been proposed to respond to necrotic cells by releasing IL-1α 
. Given that neutrophilia and pathological tissue damage, including necrosis are key hallmarks of COPD, it is plausible that IL-1α is released in COPD as a consequence of such mechanisms. We have previously shown that alveolar macrophages cultured ex vivo
from smoke-exposed animals produce significantly more IL-1α compared to controls 
. Thus, it would be of interest to examine the potential role of macrophages for contributing to IL-1α driven responses, especially given that macrophages have been suggested to be an orchestrating cell-type in COPD pathogenesis.
Our study suggests that caspase-1, the enzyme necessary for processing IL-1β into its active form 
, was dispensable for smoke-induced neutrophilic inflammation. Recently, two studies in mice showed that smoke-induced inflammation was dependent on signaling through the IL-1R1 
. While, Doz and colleagues suggested that a caspase-1 inflammasome may be important to the activation of IL-1β, Churg et al.
demonstrated using pharmacological caspase inhibitors that smoke-induced inflammation and increased serum levels of IL-1β could be attenuated. Although our observations are in contrast to those of Churg et al.
, it remains to be addressed whether differences in mouse strain, period of smoke exposure, or the specificity of the pharmacological inhibitors are contributing factors. Interestingly, Chen et al.
demonstrated in vivo
that caspase-1 was redundant in the inflammatory response to dead cells 
, suggesting that this response is dependent on IL-1α but independent of IL-1β, and that necrotic events in cigarette smoke-exposed mice may be key for driving smoke-induced neutrophilic inflammation.
Interestingly, IL-1α blockade markedly attenuated IL-1β protein levels in the lung. Although not fully understood, this is an important observation as over-expression of IL-1β has been shown to contribute to emphysematous changes in mice 
. Furthermore, a study by Castro et al.
demonstrated that smoke-induced mononuclear cell infiltrates were attenuated with an anti-IL-1β antibody therapy 
. Although IL-1β, in our model, does not appear to be necessary for cigarette smoke-induced inflammation, IL-1α up-regulation of IL-1β may provide a viable hypothesis for the difference in interventions and may potentially support the long term implications for the development of lung tissue damage in chronic pulmonary disease.
Given that the IL-1R1 was predominantly expressed on the airway epithelium and IL-1α was mainly restricted to hematopoietic cells, we addressed whether crosstalk between the hematopoietic and non-hematopoietic compartments was required for cigarette smoke-induced inflammation. Therefore, we generated IL-1R1-deficient bone marrow chimeric mice and showed that IL-1R1 signaling on non-hematopoietic structural cells, namely the alveolar epithelium, was essential for cigarette smoke-induced neutrophilic inflammation (Figure S3A
in the data supplement), while IL-1R1 signaling on hematopoietic cells (presumably macrophages and dendritic cells) was required for maximal cellular inflammation (Figure S3B
in the data supplement). Taken together, these data show that crosstalk, as depicted in Figure S3C
in the online data supplement, between IL-1α+
hematopoietic cells (such as macrophages) and IL-1R1+
lung structural cells is key for driving the inflammatory response to cigarette smoke. Although IL-1α has been shown to drive inflammation via autocrine stimulation of cells 
, expression of IL-1R1 on hematopoietic cells (such as macrophages) is only partially involved in driving smoke-induced inflammation, suggesting that activation of non-hematopoietic cells by IL-1 is critical to the infiltration of neutrophils to the lung.
We and others have previously shown that cigarette smoke exposure exacerbates the inflammatory response elicited by influenza A viruses in mice 
. Given that lung epithelial cells are the primary target of respiratory viruses, we sought to assess whether IL-1R1 dependent activation of lung resident cells was mediating the the exacerbated inflammatory response. Indeed, IL-1R1 deficiency attenuated exacerbated neutrophilic responses in cigarette smoke-exposed influenza-infected animals. Using precision cut lung slices (PCLS) we provide clear evidence that the resident cells within the smoke-exposed lung produce greater levels of neutrophil recruiting chemokines, CXCL -1, -2, and -5 in response to a dsRNA stimulus. Of note, IL-1α blocking antibodies attenuated the exacerbated inflammatory response in smoke-exposed influenza-infected mice, suggesting that IL-1α blockade, while arguably having the potential to interfere with the host response to viral infection, in fact dampened the excessive inflammation observed in these animals. In line with observations reported by Schmitz and colleagues 
, we did not detect differences in viral burden between room air wild-type and IL-1R1-deficient mice. Interestingly, while no differences were observed in viral burden in anti-IL-1α antibody treated smoke-exposed mice, an IL-1R1-deficiency increased viral burden compared to wild-type controls. While it is well understood that an IL-1R1-deficiency increases influenza-related mortality at time-points later than were assessed in this paper 
, studies are on-going to examine the outcome of IL-1α blockade to antiviral responses (later than 5 days post-infection) in smoke-exposed mice.
In COPD, chronic infiltration of the lung by neutrophils is thought to play a key part in progression of the lung obstruction due to collateral tissue damage induced by these cells. During an exacerbation, release of further pro-inflammatory mediators and an over-exuberant neutrophilic response might contribute to progression of tissue damage and increase remodeling within the lung. Therefore, attenuation of pro-inflammatory responses to viruses may under these circumstances be beneficial. Collectively, these data provide evidence that blockade of IL-1α has a potential role in limiting disease exacerbation.
The results of our study demonstrate the importance of IL-1α and its cognate receptor, IL-1R1, to the induction of cigarette smoke-induced airway inflammation, and to the exacerbation of inflammatory processes following viral infection of smoke-exposed animals. Further, we identify that this response is independent of caspase-1 and thus redundant of IL-1β signaling of its receptor. Notably, crosstalk between IL-1α+ hematopoietic cells and non-bone-marrow derived IL-1R1+ cells, was found to be essential for governing smoke-induced inflammation. Collectively, these data support a role for IL-1α/IL-1R1 therapy in the management of smoke-induced inflammation and processes driving exacerbations of COPD.