TY - JOUR
T1 - Retinoic Acid Exerts Disease Stage-Dependent Effects on Pristane-Induced Lupus
AU - Abdelhamid, Leila
AU - Cabana-Puig, Xavier
AU - Swartwout, Brianna
AU - Lee, Jiyoung
AU - Li, Song
AU - Sun, Sha
AU - Li, Yaqi
AU - Ross, A. Catharine
AU - Cecere, Thomas E.
AU - LeRoith, Tanya
AU - Werre, Stephen R.
AU - Wang, Haifeng
AU - Reilly, Christopher M.
AU - Luo, Xin M.
N1 - Funding Information:
We thank Husen Zhang for 16S rRNA sequencing analysis, Melissa Makris for the use of Flow Cytometry Core Facility, and Kristi Decourcy for the use of Fralin Imaging Core Facility at Virginia Tech. Funding. This work was supported by NIH grants AR067418 and AR073240.
Publisher Copyright:
© Copyright © 2020 Abdelhamid, Cabana-Puig, Swartwout, Lee, Li, Sun, Li, Ross, Cecere, LeRoith, Werre, Wang, Reilly and Luo.
PY - 2020/3/20
Y1 - 2020/3/20
N2 - We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.
AB - We previously showed that all-trans-retinoic acid (tRA), an active metabolite of vitamin A, exacerbated pre-existing autoimmunity in lupus; however, its effects before the development of autoimmunity are unknown. Here, using a pristane-induced model, we show that tRA exerts differential effects when given at the initiation vs. continuation phase of lupus. Unlike tRA treatment during active disease, pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow conventional dendritic cells (cDCs), and upregulating the interaction of ICAM-1 and LFA-1 in the spleen, indicating an active process of leukocyte activation and trafficking. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated the expression of genes associated with cDC activation and migration. Post-pristane tRA treatment, on the other hand, did not significantly alter the severity of glomerulonephritis; rather, it exerted immunosuppressive functions of decreasing circulatory and renal deposition of autoantibodies as well as suppressing the renal expression of proinflammatory cytokines and chemokines. Together, these findings suggest that tRA differentially modulate lupus-associated kidney inflammation depending on the time of administration. Interestingly, both pre- and post-pristane treatments with tRA reversed pristane-induced leaky gut and modulated the gut microbiota in a similar fashion, suggesting a gut microbiota-independent mechanism by which tRA affects the initiation vs. continuation phase of lupus.
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U2 - 10.3389/fimmu.2020.00408
DO - 10.3389/fimmu.2020.00408
M3 - Article
C2 - 32265909
AN - SCOPUS:85083051615
SN - 1664-3224
VL - 11
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 408
ER -