TY - JOUR
T1 - The Transcription Factor RXRa in CD11c+ APCs Regulates Intestinal Immune Homeostasis and Inflammation
AU - Manoharan, Indumathi
AU - Shanmugam, Arul Kumaran
AU - Ramalingam, Malarvizhi
AU - Patel, Nikhil
AU - Thangaraju, Muthusamy
AU - Ande, Satyanarayana
AU - Pacholczyk, Rafal
AU - Prasad, Puttur D.
AU - Manicassamy, Santhakumar
N1 - Publisher Copyright:
Copyright © 2023 by The American Association of Immunologists, Inc.
PY - 2023/9/20
Y1 - 2023/9/20
N2 - APCs such as dendritic cells and macrophages play a pivotal role in mediating immune tolerance and restoring intestinal immune homeostasis by limiting inflammatory responses against commensal bacteria. However, cell-intrinsic molecular regulators critical for programming intestinal APCs to a regulatory state rather than an inflammatory state are unknown. In this study, we report that the transcription factor retinoid X receptor a (RXRa) signaling in CD11c+ APCs is essential for suppressing intestinal inflammation by imparting an anti-inflammatory phenotype. Using a mouse model of ulcerative colitis, we demonstrated that targeted deletion of RXRa in CD11c+ APCs in mice resulted in the loss of T cell homeostasis with enhanced intestinal inflammation and increased histopathological severity of colonic tissue. This was due to the increased production of proinflammatory cytokines that drive Th1/Th17 responses and decreased expression of immune-regulatory factors that promote regulatory T cell differentiation in the colon. Consistent with these findings, pharmacological activation of the RXRa pathway alleviated colitis severity in mice by suppressing the expression of inflammatory cytokines and limiting Th1/Th17 cell differentiation. These findings identify an essential role for RXRa in APCs in regulating intestinal immune homeostasis and inflammation. Thus, manipulating the RXRa pathway could provide novel opportunities for enhancing regulatory responses and dampening colonic inflammation.
AB - APCs such as dendritic cells and macrophages play a pivotal role in mediating immune tolerance and restoring intestinal immune homeostasis by limiting inflammatory responses against commensal bacteria. However, cell-intrinsic molecular regulators critical for programming intestinal APCs to a regulatory state rather than an inflammatory state are unknown. In this study, we report that the transcription factor retinoid X receptor a (RXRa) signaling in CD11c+ APCs is essential for suppressing intestinal inflammation by imparting an anti-inflammatory phenotype. Using a mouse model of ulcerative colitis, we demonstrated that targeted deletion of RXRa in CD11c+ APCs in mice resulted in the loss of T cell homeostasis with enhanced intestinal inflammation and increased histopathological severity of colonic tissue. This was due to the increased production of proinflammatory cytokines that drive Th1/Th17 responses and decreased expression of immune-regulatory factors that promote regulatory T cell differentiation in the colon. Consistent with these findings, pharmacological activation of the RXRa pathway alleviated colitis severity in mice by suppressing the expression of inflammatory cytokines and limiting Th1/Th17 cell differentiation. These findings identify an essential role for RXRa in APCs in regulating intestinal immune homeostasis and inflammation. Thus, manipulating the RXRa pathway could provide novel opportunities for enhancing regulatory responses and dampening colonic inflammation.
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U2 - 10.4049/jimmunol.2200909
DO - 10.4049/jimmunol.2200909
M3 - Article
C2 - 37477694
AN - SCOPUS:85168427558
SN - 0022-1767
VL - 211
SP - 853
EP - 861
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -