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Retinoic acid can exacerbate T cell intrinsic TLR2 activation to promote tolerance.

Nguyen V, Pearson K, Kim JH, Kamdar K, DePaolo RW - PLoS ONE (2015)

Bottom Line: Here, we found that treatment with RA can dampen inflammation during intestinal injury.Our data demonstrate that RA treatment enhances TLR2-dependent IL-10 production from T cells and this, in turn, potentiates T regulatory cell (TREG) generation without the need for activation of antigen presenting cells.These data also suggest that combinatorial therapy using RA and TLR2 ligands may be advantageous in the design of therapies to treat autoimmune or inflammatory disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Gastroenterology and Nutrition, Children's Hospital of Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
The contribution of vitamin A to immune health has been well established. However, recent evidence indicates that its active metabolite, retinoic acid (RA), has the ability to promote both tolerogenic and inflammatory responses. While the outcome of RA-mediated immunity is dependent upon the immunological status of the tissue, the contribution of specific innate signals influencing this response have yet to be delineated. Here, we found that treatment with RA can dampen inflammation during intestinal injury. Importantly, we report a novel and unexpected requirement for TLR2 in RA-mediated suppression. Our data demonstrate that RA treatment enhances TLR2-dependent IL-10 production from T cells and this, in turn, potentiates T regulatory cell (TREG) generation without the need for activation of antigen presenting cells. These data also suggest that combinatorial therapy using RA and TLR2 ligands may be advantageous in the design of therapies to treat autoimmune or inflammatory disease.

No MeSH data available.


Related in: MedlinePlus

RA potentiates colonic injury and inflammation in the absence of TLR2 signaling.WT and TLR2KO mice were given 2.5% DSS for seven days to induce colonic damage and then placed on normal drinking water for seven days to allow for tissue repair. Upon first presence of fecal occult blood positivity for each, mice were supplemented with RA or vehicle control, which continued for the rest of the disease course. Weight loss (A) and fecal occult blood (B) (n = 10–14 mice per group) were monitored daily. (C) H&E staining of colonic sections of mice at day 14 (after 7 days of DSS followed by 7 days of water). (D) Histology scoring of H&E-stained colonic slides (n = 4 mice per group). (E) The percent of surface area containing ulcerated/denuded epithelium quantified using J Image software. (F) Colon lengths from mice at day 10 (n = 5–6 mice per group). *, p < 0.05, **, p < 0.01 using Students t-test.
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pone.0118875.g001: RA potentiates colonic injury and inflammation in the absence of TLR2 signaling.WT and TLR2KO mice were given 2.5% DSS for seven days to induce colonic damage and then placed on normal drinking water for seven days to allow for tissue repair. Upon first presence of fecal occult blood positivity for each, mice were supplemented with RA or vehicle control, which continued for the rest of the disease course. Weight loss (A) and fecal occult blood (B) (n = 10–14 mice per group) were monitored daily. (C) H&E staining of colonic sections of mice at day 14 (after 7 days of DSS followed by 7 days of water). (D) Histology scoring of H&E-stained colonic slides (n = 4 mice per group). (E) The percent of surface area containing ulcerated/denuded epithelium quantified using J Image software. (F) Colon lengths from mice at day 10 (n = 5–6 mice per group). *, p < 0.05, **, p < 0.01 using Students t-test.

Mentions: Due to the prevalence of vitamin and micronutrient deficiencies in patients with IBD, enteral repletion is often initiated at the time of diagnosis [8]. Given the potential for RA to promote either regulatory [13,19,23] or inflammatory [24,33] immune responses depending on the status of the tissue microenvironment, we assessed the effects of RA supplementation during acute colitis and evaluated the role of TLR2 in modulating these effects. DSS was administered to WT and TLR2 deficient mice to induce epithelial injury for seven days followed by a repair phase in which the mice received regular drinking water. In order to mirror the clinical presentation and course of individuals with IBD, we delayed enteral supplementation of RA until overt signs of colitis (i.e. loose stool and fecal occult blood) were noted. In line with prior studies demonstrating that the absence of TLR2 signaling exacerbates chemically-induced and spontaneous colitis in mice, we found that TLR2KO mice lost more body weight than WT counterparts during induction of colitis as well as during recovery [43,44] (Fig 1A, closed and open circles). TLR2KO mice also had significantly worse fecal occult blood scores (Fig 1B, closed and open circles), and worse histopathology (Fig 1C) compared to WT mice, with larger areas of denuded, ulcerated epithelium (Fig 1D and 1E, white bars, closed and open circles) and shorter colon lengths (Fig 1F), indicative of inflammation. WT mice treated with RA showed significant improvement in fecal occult bleeding (Fig 1B, closed squares), histopathology (Fig 1C, bottom left), less epithelial damage (Fig 1D and 1E, black bar and closed squares) and significantly longer colons (Fig 1F). In contrast, RA supplementation had adverse effects in TLR2KO mice, which demonstrated severe rectal bleeding (Fig 1B, open squares); worse histopathology (Fig 1C and 1D, bottom right, black bars), and shorter colons (Fig 1F) compared to both WT mice receiving RA and TLR2KO mice receiving vehicle control. Together these data demonstrate that treatment with RA can protect against epithelial injury during acute colitis however, in the absence of TLR2, treatment with RA exacerbates disease.


Retinoic acid can exacerbate T cell intrinsic TLR2 activation to promote tolerance.

Nguyen V, Pearson K, Kim JH, Kamdar K, DePaolo RW - PLoS ONE (2015)

RA potentiates colonic injury and inflammation in the absence of TLR2 signaling.WT and TLR2KO mice were given 2.5% DSS for seven days to induce colonic damage and then placed on normal drinking water for seven days to allow for tissue repair. Upon first presence of fecal occult blood positivity for each, mice were supplemented with RA or vehicle control, which continued for the rest of the disease course. Weight loss (A) and fecal occult blood (B) (n = 10–14 mice per group) were monitored daily. (C) H&E staining of colonic sections of mice at day 14 (after 7 days of DSS followed by 7 days of water). (D) Histology scoring of H&E-stained colonic slides (n = 4 mice per group). (E) The percent of surface area containing ulcerated/denuded epithelium quantified using J Image software. (F) Colon lengths from mice at day 10 (n = 5–6 mice per group). *, p < 0.05, **, p < 0.01 using Students t-test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380421&req=5

pone.0118875.g001: RA potentiates colonic injury and inflammation in the absence of TLR2 signaling.WT and TLR2KO mice were given 2.5% DSS for seven days to induce colonic damage and then placed on normal drinking water for seven days to allow for tissue repair. Upon first presence of fecal occult blood positivity for each, mice were supplemented with RA or vehicle control, which continued for the rest of the disease course. Weight loss (A) and fecal occult blood (B) (n = 10–14 mice per group) were monitored daily. (C) H&E staining of colonic sections of mice at day 14 (after 7 days of DSS followed by 7 days of water). (D) Histology scoring of H&E-stained colonic slides (n = 4 mice per group). (E) The percent of surface area containing ulcerated/denuded epithelium quantified using J Image software. (F) Colon lengths from mice at day 10 (n = 5–6 mice per group). *, p < 0.05, **, p < 0.01 using Students t-test.
Mentions: Due to the prevalence of vitamin and micronutrient deficiencies in patients with IBD, enteral repletion is often initiated at the time of diagnosis [8]. Given the potential for RA to promote either regulatory [13,19,23] or inflammatory [24,33] immune responses depending on the status of the tissue microenvironment, we assessed the effects of RA supplementation during acute colitis and evaluated the role of TLR2 in modulating these effects. DSS was administered to WT and TLR2 deficient mice to induce epithelial injury for seven days followed by a repair phase in which the mice received regular drinking water. In order to mirror the clinical presentation and course of individuals with IBD, we delayed enteral supplementation of RA until overt signs of colitis (i.e. loose stool and fecal occult blood) were noted. In line with prior studies demonstrating that the absence of TLR2 signaling exacerbates chemically-induced and spontaneous colitis in mice, we found that TLR2KO mice lost more body weight than WT counterparts during induction of colitis as well as during recovery [43,44] (Fig 1A, closed and open circles). TLR2KO mice also had significantly worse fecal occult blood scores (Fig 1B, closed and open circles), and worse histopathology (Fig 1C) compared to WT mice, with larger areas of denuded, ulcerated epithelium (Fig 1D and 1E, white bars, closed and open circles) and shorter colon lengths (Fig 1F), indicative of inflammation. WT mice treated with RA showed significant improvement in fecal occult bleeding (Fig 1B, closed squares), histopathology (Fig 1C, bottom left), less epithelial damage (Fig 1D and 1E, black bar and closed squares) and significantly longer colons (Fig 1F). In contrast, RA supplementation had adverse effects in TLR2KO mice, which demonstrated severe rectal bleeding (Fig 1B, open squares); worse histopathology (Fig 1C and 1D, bottom right, black bars), and shorter colons (Fig 1F) compared to both WT mice receiving RA and TLR2KO mice receiving vehicle control. Together these data demonstrate that treatment with RA can protect against epithelial injury during acute colitis however, in the absence of TLR2, treatment with RA exacerbates disease.

Bottom Line: Here, we found that treatment with RA can dampen inflammation during intestinal injury.Our data demonstrate that RA treatment enhances TLR2-dependent IL-10 production from T cells and this, in turn, potentiates T regulatory cell (TREG) generation without the need for activation of antigen presenting cells.These data also suggest that combinatorial therapy using RA and TLR2 ligands may be advantageous in the design of therapies to treat autoimmune or inflammatory disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Gastroenterology and Nutrition, Children's Hospital of Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
The contribution of vitamin A to immune health has been well established. However, recent evidence indicates that its active metabolite, retinoic acid (RA), has the ability to promote both tolerogenic and inflammatory responses. While the outcome of RA-mediated immunity is dependent upon the immunological status of the tissue, the contribution of specific innate signals influencing this response have yet to be delineated. Here, we found that treatment with RA can dampen inflammation during intestinal injury. Importantly, we report a novel and unexpected requirement for TLR2 in RA-mediated suppression. Our data demonstrate that RA treatment enhances TLR2-dependent IL-10 production from T cells and this, in turn, potentiates T regulatory cell (TREG) generation without the need for activation of antigen presenting cells. These data also suggest that combinatorial therapy using RA and TLR2 ligands may be advantageous in the design of therapies to treat autoimmune or inflammatory disease.

No MeSH data available.


Related in: MedlinePlus