Paradoxical Effects of All-Trans-Retinoic Acid on Lupus-Like Disease in the MRL/lpr Mouse Model

Abstract

Roles of all-trans-retinoic acid (tRA), a metabolite of vitamin A (VA), in both tolerogenic and immunogenic responses are documented. However, how tRA affects the development of systemic autoimmunity is poorly understood. Here we demonstrate that tRA have paradoxical effects on the development of autoimmune lupus in the MRL/lpr mouse model. We administered, orally, tRA or VA mixed with 10% of tRA (referred to as VARA) to female mice starting from 6 weeks of age. At this age, the mice do not exhibit overt clinical signs of lupus. However, the immunogenic environment preceding disease onset has been established as evidenced by an increase of total IgM/IgG in the plasma and expansion of lymphocytes and dendritic cells in secondary lymphoid organs. After 8 weeks of tRA, but not VARA treatment, significantly higher pathological scores in the skin, brain and lung were observed. These were accompanied by a marked increase in B-cell responses that included autoantibody production and enhanced expression of plasma cell-promoting cytokines. Paradoxically, the number of lymphocytes in the mesenteric lymph node decreased with tRA that led to significantly reduced lymphadenopathy. In addition, tRA differentially affected renal pathology, increasing leukocyte infiltration of renal tubulointerstitium while restoring the size of glomeruli in the kidney cortex. In contrast, minimal induction of inflammation with tRA in the absence of an immunogenic environment in the control mice was observed. Altogether, our results suggest that under a predisposed immunogenic environment in autoimmune lupus, tRA may decrease inflammation in some organs while generating more severe disease in others.

Transcription factor ISX mediates the cross talk between diet and immunity

“…Though we did not clarify all molecular details, our data suggested that the loss of the ISX-dependent control of provitamin A metabolism triggered this pathology. This conclusion conforms to results from other studies, which demonstrate that excessive amounts of performed retinoids can promote inflammation and can trigger loss of tolerance at the intestinal barrier (20,36). Such failure to establish tolerance against commensal flora and food antigens has been implicated in the autoimmunity that underlies type 1 diabetes (26).…”

Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses

“…Serum was collected and stored at 2808C. Detection of anti-double-stranded DNA (dsDNA) IgG was described previously [21]. A similar procedure was used to detect anti-dsDNA IgG2a.…”

Cutting Edge: Plasmacytoid Dendritic Cells in Late-Stage Lupus Mice Defective in Producing IFN-α

“…MRL mice carry wild-type Fas and display lupus much later than do lpr mice. They appear normal at 6 wk and are considered to be at predisease stage at 16 wk (29). Therefore, our mouse groups included 16-wk-old lpr (late-stage lupus), 6 wk-old lpr and 16-wk-old MRL (predisease), and 6-wk-old MRL mice (control).…”

“…Therefore, our mouse groups included 16-wk-old lpr (late-stage lupus), 6 wk-old lpr and 16-wk-old MRL (predisease), and 6-wk-old MRL mice (control). Although mouse pDCs are most enriched in the bone marrow compared with other organs, they are still a minor population in the bone marrow (29). Rigorous quality control measures were taken to ensure accurate processing of samples.…”

“…This suggests that pDCs produce a large amount of IFN-a to initiate the disease. Although the bone marrow has the highest percentage of pDCs (29), lpr mice with late-stage disease possess very large lymph nodes, increasing the absolute numbers of pDCs. Indeed, we found that pDCs were primarily found in lymph nodes in 16-wk-old lpr mice (Fig.…”