Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection

Jennifer Kearley; Jonathan S Silver; Caroline Sanden; Zheng Liu; Aaron A Berlin; Natalie White; Michiko Mori; Tuyet-Hang Pham; Christine K Ward; Gerard J Criner; Nathaniel Marchetti; Tomas Mustelin; Jonas S Erjefalt; Roland Kolbeck; Alison A Humbles

doi:10.1016/j.immuni.2015.02.011

Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection

Immunity. 2015 Mar 17;42(3):566-79. doi: 10.1016/j.immuni.2015.02.011.

Authors

Affiliations

¹ Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA.
² Department of Experimental Medical Science, Lund University, Lund 22184, Sweden.
³ Department of Translational Sciences, MedImmune LLC, Gaithersburg, MD 20878, USA.
⁴ Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
⁵ Department of Respiratory, Inflammation and Autoimmunity, MedImmune LLC, Gaithersburg, MD 20878, USA. Electronic address: humblesa@medimmune.com.

PMID: 25786179
DOI: 10.1016/j.immuni.2015.02.011

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Gene Expression Regulation
Humans
Immunity, Innate / drug effects*
Influenza A virus / immunology
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukins / deficiency
Interleukins / genetics
Interleukins / immunology*
Killer Cells, Natural / immunology
Killer Cells, Natural / pathology
Lung / drug effects
Lung / immunology
Lung / pathology
Lymphocytes / drug effects
Lymphocytes / immunology
Lymphocytes / pathology
Macrophages / immunology
Macrophages / pathology
Mice, Transgenic
Nicotiana / chemistry
Orthomyxoviridae Infections / etiology
Orthomyxoviridae Infections / genetics
Orthomyxoviridae Infections / immunology*
Orthomyxoviridae Infections / pathology
Pulmonary Disease, Chronic Obstructive / genetics
Pulmonary Disease, Chronic Obstructive / immunology*
Pulmonary Disease, Chronic Obstructive / pathology
Receptors, Interleukin / deficiency
Receptors, Interleukin / genetics
Receptors, Interleukin / immunology*
Respiratory Mucosa / drug effects
Respiratory Mucosa / immunology
Respiratory Mucosa / pathology
Signal Transduction
Smoke / adverse effects*
Weight Loss

Substances

Il1rl1 protein, mouse
Il33 protein, mouse
Interleukin-1 Receptor-Like 1 Protein
Interleukin-33
Interleukins
Receptors, Interleukin
Smoke

Associated data

GEO/GSE66492