Retinoic acid exerts disease stage-dependent and tissue-specific effects on pristane-induced lupus

We previously showed that all-trans-retinoic acid (tRA) exacerbated pre-existing autoimmunity in lupus; however, its effects before disease onset are unknown. Here, using a pristane-induced model, we show that tRA exerts tissue-specific effects when given at the initiation vs. continuation phase of lupus. Pre-pristane treatment with tRA aggravated glomerulonephritis through increasing renal expression of pro-fibrotic protein laminin β1, activating bone marrow CD11b- conventional dendritic cells, increasing the splenic CD4:CD8 ratio, and upregulating the interaction of ICAM-1 and LFA-1 that led to the infiltration of inflammatory cells to the spleen. Transcriptomic analysis revealed that prior to lupus induction, tRA significantly upregulated genes associated with cell differentiation, activation, and migration. Moreover, compared to pristane alone, tRA pre-treatment potentiated, whereas tRA post-treatment significantly suppressed, the renal expression of proinflammatory TNF-α, IL-1β, CCL2, and CCL3. While it may benefit the kidney, post-pristane treatment with tRA worsened the onset and severity of pristane-induced arthritis through promoting neutrophil and mononuclear cell infiltration into the joints. Together, these findings suggest that tRA supplementation regardless of the time of administration promotes chemokine-driven migration and tissue-specific infiltration of inflammatory cells, thereby exacerbating lupus-associated kidney or joint inflammation. Interestingly, both pre- and post-treatments with tRA 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.