IL-1α/IL-1R1 Expression in Chronic Obstructive Pulmonary Disease and Mechanistic Relevance to Smoke-Induced Neutrophilia in Mice

Abstract

BackgroundCigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood.Methodology and Principal FindingsThe objective of this study was to assess IL-1 α and β expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation. Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1α and β. Here, we demonstrate an underappreciated role for IL-1α expression in COPD. While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1α was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1α/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation.Conclusions and SignificanceThis study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.

Cigarette Smoke Primes the Pulmonary Environment to IL-1α/CXCR-2–Dependent Nontypeable Haemophilus influenzae–Exacerbated Neutrophilia in Mice

“…Our previous data suggest the importance of structural cells in neutrophil recruitment (18), such as epithelial cells. It would be an intuitive supposition that these epithelial cells could be a source of neutrophil recruiting chemokines such as CXCL5.…”

“…Lung slices were generated as described previously (18). Briefly, lungs were inflated with 37˚C agarose (Sigma-Aldrich) prepared to 2% in HBSS supplemented with HEPES (Sigma-Aldrich).…”

“…Animal models have identified the importance of IL-1R1 signaling to neutrophilic inflammation elicited by cigarette smoke (18)(19)(20). The cytokines IL-1a and IL-1b activate IL-1R1 (21).…”

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

“…These particles and micrometer-sized crystals, such as alum and silica, which are considered Th2-inducing adjuvants, induce inflammasome-dependent IL-1b and IL-18 production (26). Furthermore, particles can induce cellular damage, resulting in the release of alarmins, including IL-1a (52). Although the involvement of IL-1 family cytokines in particulate matterinduced Th2 responses is controversial (26), IL-1 family cytokines might participate in IgE and IgG1 production in the lungs (37)(38)(39)(40)53).…”

NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating the IL-1α/G-CSF axis

“…19 IL-1a is highly associated with neutrophilic inflammation, and this function, in many settings, is not redundant with IL-1b. This includes neutrophil recruitment in response to necrotic cells, 22 chronic obstructive pulmonary disease (COPD), 49 hypoxic tissue injury, 50 atherosclerosis, 51 neutrophilic dermatosis secondary to a mutant Src homology region 2 domain-containing phosphatase-1 phosphatase, 52 adenovirus-induced splenic inflammation, 53,54 and Legionella pneumophila pneumonia. 55 We show that the mechanistic link between IL-1a and neutrophil extravasation in response to DAMPassociated tissue injury is mediated by IL-1a-induced production of G-CSF, which acts systemically to rapidly mobilize neutrophils from the marrow storage pool into circulation.…”