IL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration

Rania Dagher, Alan M. Copenhaver, Valerie Besnard, Aaron Berlin, Fatima Hamidi, Marielle Maret, Jingya Wang, Xiaotao Qu, Yashaswi Shrestha, Jincheng Wu, Gregory Gautier, Rajiv Raja, Michel Aubier, Roland Kolbeck, Alison A. Humbles () and Marina Pretolani ()
Additional contact information
Rania Dagher: Inserm UMR1152—Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris
Alan M. Copenhaver: Bioscience COPD/IPF, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca
Valerie Besnard: Inserm UMR1152—Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris
Aaron Berlin: Bioscience COPD/IPF, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca
Fatima Hamidi: Inserm UMR1152—Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris
Marielle Maret: Inserm UMR1152—Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris
Jingya Wang: Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca
Xiaotao Qu: Data Sciences and AI, BioPharmaceuticals R&D, AstraZeneca
Yashaswi Shrestha: Translational Medicine, Oncology R&D, AstraZeneca
Jincheng Wu: Data Sciences and AI, BioPharmaceuticals R&D, AstraZeneca
Gregory Gautier: Faculté de Médecine, Université Paris
Rajiv Raja: Translational Medicine, Oncology R&D, AstraZeneca
Michel Aubier: Inserm UMR1152—Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris
Roland Kolbeck: Bioscience COPD/IPF, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca
Alison A. Humbles: Bioscience COPD/IPF, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca
Marina Pretolani: Inserm UMR1152—Physiopathologie et Epidémiologie des Maladies Respiratoires, Université Paris

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract Evidence points to an indispensable function of macrophages in tissue regeneration, yet the underlying molecular mechanisms remain elusive. Here we demonstrate a protective function for the IL-33-ST2 axis in bronchial epithelial repair, and implicate ST2 in myeloid cell differentiation. ST2 deficiency in mice leads to reduced lung myeloid cell infiltration, abnormal alternatively activated macrophage (AAM) function, and impaired epithelial repair post naphthalene-induced injury. Reconstitution of wild type (WT) AAMs to ST2-deficient mice completely restores bronchial re-epithelialization. Central to this mechanism is the direct effect of IL-33-ST2 signaling on monocyte/macrophage differentiation, self-renewal and repairing ability, as evidenced by the downregulation of key pathways regulating myeloid cell cycle, maturation and regenerative function of the epithelial niche in ST2−/− mice. Thus, the IL-33-ST2 axis controls epithelial niche regeneration by activating a large multi-cellular circuit, including monocyte differentiation into competent repairing AAMs, as well as group-2 innate lymphoid cell (ILC2)-mediated AAM activation.

Date: 2020
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DOI: 10.1038/s41467-020-18466-w

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