Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells.
BACKGROUND
Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33.


OBJECTIVE
We sought to test the hypothesis that pulmonary RAGE is necessary for allergen-induced ILC2 accumulation in the lung.


METHODS
AAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses.


RESULTS
RAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33-induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract.


CONCLUSIONS
For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Elizabeth A
EA
Oczypok
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Pavle S
PS
Milutinovic
Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pa.
John F
JF
Alcorn
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Anupriya
A
Khare
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Lauren T
LT
Crum
Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, Pa.
Michelle L
ML
Manni
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pa.
Michael W
MW
Epperly
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Adriane M
AM
Pawluk
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
Anuradha
A
Ray
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. Electronic address: tdoury@pitt.edu.
Tim D
TD
Oury
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000528:Alternaria / Q000737:chemistry; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage / Q000276:immunology; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D041981:Gastrointestinal Tract / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33 / Q000235:genetics / Q000276:immunology*; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009928:Organ Specificity; D010537:Peritoneum / Q000276:immunology / Q000473:pathology; D039981:Pyroglyphidae / Q000737:chemistry; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology; D018183:Transplantation Chimera
C000593873:Ager protein, mouse; D000485:Allergens; D039741:Antigens, Dermatophagoides; C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D015848:Interleukin-5; D000067759:Receptor for Advanced Glycation End Products
Asthma; IL-33; group 2 innate lymphoid cells; receptor for advanced glycation end-products