GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R.
Obesity and diabetes are characterized by increased inflammation reflecting disordered control of innate immunity. We reveal a local intestinal intraepithelial lymphocyte (IEL)-GLP-1 receptor (GLP-1R) signaling network that controls mucosal immune responses. Glp1r expression was enriched in intestinal IEL preparations and copurified with markers of Tαβ and Tγδ IELs, the two main subsets of intestinal IELs. Exendin-4 increased cAMP accumulation in purified IELs and reduced the production of cytokines from activated IELs but not from splenocytes ex vivo. These actions were mimicked by forskolin, absent in IELs from Glp1r(-/-) mice, and attenuated by the GLP-1R agonist exendin (9-39) consistent with a GLP-1R-dependent mechanism of action. Furthermore, Glp1r(-/-) mice exhibited dysregulated intestinal gene expression, an abnormal representation of microbial species in feces, and enhanced sensitivity to intestinal injury following administration of dextran sodium sulfate. Bone marrow transplantation using wild-type C57BL/6 donors normalized expression of multiple genes regulating immune function and epithelial integrity in Glp1r(-/-) recipient mice, whereas acute exendin-4 administration robustly induced the expression of genes encoding cytokines and chemokines in normal and injured intestine. Taken together, these findings define a local enteroendocrine-IEL axis linking energy availability, host microbial responses, and mucosal integrity to the control of innate immunity.
Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
Bernardo
B
Yusta
Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
Laurie L
LL
Baggio
Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
Jacqueline
J
Koehler
Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
Dianne
D
Holland
Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
Xiemin
X
Cao
Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Lee J
LJ
Pinnell
Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Kathene C
KC
Johnson-Henry
Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
William
W
Yeung
Department of Medicine, Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
Michael G
MG
Surette
Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada.
K W Annie
KW
Bang
Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
Philip M
PM
Sherman
Department of Medicine, Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute, Toronto, ON, Canada drucker@lunenfeld.ca.
Daniel J
DJ
Drucker
D000818:Animals; D016207:Cytokines / Q000032:analysis; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists* / Q000502:physiology*; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology
D016207:Cytokines; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide