IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation.
Alternatively activated macrophages (AAM) play a crucial role in type 2 immunity. Mice deficient in ST2, a receptor for the latest member of the IL-1 family, IL-33, have impaired type 2 immune responses. We therefore reasoned that IL-33/ST2 signaling may be involved in the differentiation and activation of AAM during airway inflammation. We report here that IL-33 changed the quiescent phenotype of alveolar macrophages toward an AAM phenotype that expressed mannose receptor, IL-4Ralpha, and produced high levels of CCL24 and CCL17 in an IL-13-dependent manner during IL-33-induced airway inflammation. Neutralization of AAM-derived CCL24 led to an amelioration of IL-33-induced eosinophilia in the lungs. Moreover, depletion of alveolar macrophages reduced IL-33-induced airway inflammation. Additionally, the attenuated OVA-induced airway inflammation in ST2(-/-) mice was associated with a decrease in AAM differentiation. In vitro, IL-33 amplified IL-13-induced polarization of alveolar- and bone marrow-derived macrophage toward an AAM phenotype by increasing the expression of arginase I, Ym1, as well as the production of CCL24 and CCL17. IL-13/IL-4Ralpha signaling was crucial for IL-33-driven AAM amplification by inducing the expression of ST2L. Finally, we showed that IL-33 was more abundantly expressed in the lung epithelial cells of asthma patients than those from healthy controls, suggesting that IL-33 may be involved in lung macrophage activation in clinical asthma. Taken together, we demonstrate here that IL-33/ST2 plays a significant role in the amplification of AAM polarization and chemokine production which contribute to innate and Ag-induced airway inflammation.
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom.
Mariola
M
Kurowska-Stolarska
Bartosz
B
Stolarski
Peter
P
Kewin
Grace
G
Murphy
Christopher J
CJ
Corrigan
Sun
S
Ying
Nick
N
Pitman
Ananda
A
Mirchandani
Batika
B
Rana
Nico
N
van Rooijen
Malcolm
M
Shepherd
Charlie
C
McSharry
Iain B
IB
McInnes
Damo
D
Xu
Foo Y
FY
Liew
D000328:Adult; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D016764:Cell Polarity / Q000276:immunology*; D054414:Chemokine CCL17 / Q000276:immunology / Q000378:metabolism; D054423:Chemokine CCL24 / Q000276:immunology / Q000378:metabolism; D004802:Eosinophilia / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D010047:Ovalbumin / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D054414:Chemokine CCL17; D054423:Chemokine CCL24; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; C530318:ST2L protein, mouse; D015847:Interleukin-4; D010047:Ovalbumin