Cigarette Smoke Silences Innate Lymphoid Cell... : Immunity (original) (raw)

SUMMARY

Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.

Highlights

• IL-33 is upregulated by cigarette smoke and released in response to virus infection
• Smoke dampens ST2 expression on ILC2s but enhances ST2 on NK cells and macrophages
• IL-33 drives an exacerbated Th1-cell-like inflammatory response to virus infection
• IL-33 might play a critical role in pathogen-induced exacerbations of COPD

In Brief

Smoking is thought to be central to the altered responsiveness to infection in patients with chronic obstructive pulmonary disease (COPD). Humbles and colleagues show that mice lacking interleukin-33 (IL-33) are protected from smoke-induced exaggerated inflammatory responses to virus infection, suggesting that IL-33 is a critical mediator in acute exacerbations of COPD.