Smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection
【LWBS 2015 03 19 A】(SpringRain edited from Immunity) Chronic obstructive pulmonary disease (COPD) is a lung disorder defined by irreversible and progressive airflow obstruction. Acute exacerbations in COPD are associated with viral and/or bacterial infections. Frequent exacerbations accelerate disease progression, impair quality of life, increase the risk of hospitalization, and are a major cause of mortality in these patients. Further, they are characteristically more severe, prolonged, and associated with enhanced inflammatory responses.
Cigarette smoke exposure has a major impact on respiratory health and is considered to be the primary causative agent in COPD. How smoking alters the immune system and leads to a chronic and poorly controlled inflammatory disease is the subject of intense investigation. Infection of mice on a background of smoke results in exaggerated inflammation and delayed resolution, and several studies have implicated a role for the interleukin-1 (IL-1) family members IL-1α and IL-18 in COPD and corresponding mouse models.
IL-33 is a largely stromal-derived cytokine belonging to the IL-1 family and is primarily associated with T helper 2 (Th2) cell immunity via induction of IL-13, from type 2 innate lymphoid cells (ILCs) and Th2 cells. The IL-33/ST2 axis has been implicated in a number of inflammatory settings including asthma, influenza-associated airway hyperactivity (AHR), and allergic rhinitis; however, more recently a role for this pathway has been shown in non Th2-like diseases, such as rheumatoid arthritis, inflammatory bowel disease, and pain. Although not defined, release of this cytokine is thought to be mainly triggered via cell necrosis/damage. Notably, airway damage is a hallmark of COPD and is associated with prolonged exposure to cigarette smoke and microbial pathogens. A recent study showed that IL-33 is elevated in severe COPD and is associated with an IL-13- and mucin gene-like signature.
In this study, the authors have used a combination of cigarette smoke and infection to model exacerbations of COPD in mice and shown that on the background of smoke exposure, exaggerated inflammation to infection is completely attenuated in the absence of IL-33 signaling. Mechanistically, exacerbation entailed a two-step process, whereby smoke enhanced epithelial expression of IL-33 and virus-mediated damage induced release, leading to an IL-33-dependent amplification of anti-viral immunity. Importantly, smoke exposure impaired the ability of the lung to mount a Th2 cell response by suppressing ST2 expression and subsequent IL-13 production in ILC2s, while simultaneously increasing ST2 levels on NK cells and macrophages. This facilitated a synergistic response to IL-33 in these cells, resulting in elevated concentrations of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), IL-12, and interferon-γ (IFN-γ) and exaggerated Th1-like inflammation. Lastly, they extended the findings to human COPD and show that elevated epithelial IL-33 concentrations correlate with disease severity and that viral infection induces significant IL-33 release from human bronchial epithelial cells.
This study provides insight into how smoking might influence susceptibility to recurrent infection in COPD and suggests that therapeutic intervention of the IL-33 pathway might be of benefit in disease.(LiveWell-BioScience.com)