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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Enterocolitis causes profound lymphoid depletion in endothelin receptor B- and endothelin 3-null mouse models of
Philip K Frykman1, Zhi Cheng, Xiao Wang
1Division of Pediatric Surgery and The Pediatric Surgery Laboratory, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Insights
Hirschsprung disease (HSCR) enterocolitis causes immune abnormalities, including splenic lymphopenia, in mice. These immune defects stem from colonic aganglionosis, not direct lymphoid organ signaling issues, with corticosterone as a potential mediator.
Area of Science:
- Immunology
- Developmental Biology
- Gastroenterology
Background:
- Enterocolitis is a severe complication of Hirschsprung disease (HSCR), a congenital condition affecting the colon.
- Immune dysregulation, specifically splenic lymphopenia, is observed in mouse models of HSCR.
- The underlying mechanisms linking HSCR to immune dysfunction remain largely unknown.
Purpose of the Study:
- To elucidate the molecular mechanisms responsible for the immune phenotype observed in HSCR mouse models.
- To determine if the immune abnormalities in HSCR are a direct consequence of lymphoid organ defects or secondary to colonic aganglionosis.
Main Methods:
- Utilized Endothelin Receptor B (Ednrb)-null and Edn3-null mouse models of HSCR.
- Performed adoptive transfer experiments using Ednrb(-/-) bone marrow into RAG2-null mice.
- Analyzed thymic involution, splenic lymphopenia, and B lymphopoiesis.
Main Results:
- Enterocolitis in Ednrb(-/-) and Edn3(-/-) mice resulted in thymic involution, splenic lymphopenia, and suppressed B lymphopoiesis.
- These immune changes were linked to colonic aganglionosis, not intrinsic defects in Endothelin signaling within lymphoid organs.
- Adoptive transfer of Ednrb(-/-) marrow into RAG2-null mice restored lymphoid organs without inducing enterocolitis.
- Elevated corticosterone levels were identified as a potential mediator of the observed immune phenotype.
Conclusions:
- The immune abnormalities in HSCR mouse models are a consequence of colonic aganglionosis and associated physiological stress, rather than a primary lymphoid organ defect.
- Corticosterone is implicated as a key mediator in the development of immune suppression during HSCR-related enterocolitis.
- This HSCR mouse model offers a valuable platform for studying immune responses during severe physiological stress, akin to neonatal sepsis.
Abstract:
Potentially life-threatening enterocolitis is the most frequent complication in children with colonic aganglionosis (Hirschsprung disease, HSCR), and little is known about the mechanisms leading to enterocolitis. Splenic lymphopenia has been reported in the Endothelin Receptor B (Ednrb)-null mouse model of HSCR that develops enterocolitis. In this study, we sought to identify molecular mechanisms underlying this immune phenotype. We employed the Ednrb(-/-) mouse, and the knockout of its ligand, Edn3 (Edn3(-/-)). The major finding is that enterocolitis in the Ednrb(-/-) and Edn3(-/-) mice lead to thymic involution, splenic lymphopenia, and suppression of B lymphopoiesis as a consequence of colonic aganglionosis, not an intrinsic Edn3-Ednrb signaling defect directly affecting the lymphoid organs. We showed that adoptive transfer of Ednrb(-/-) marrow repopulated the RAG2-null mice marrow, thymus and spleen without development of enterocolitis. We identified the glucocorticoid corticosterone, as a potential mediator of the immune phenotype. This previously unrecognized pattern of immune abnormalities in mouse is nearly identical to lymphoid depletion in neonatal sepsis during severe physiological stress, suggesting that the mouse model used here could be also used for sepsis studies.
