L-fucose reduces gut inflammation due to T-regulatory response in Muc2 null mice

<p>Fucose, the terminal glycan of the intestinal glycoprotein Mucin2, was shown to have an<br> anti-inflammatory effect in mouse colitis models and modulate immune response due to<br> macrophage polarization changes. In this study we evaluated the effect of 0.05% L-fucose<br> supplementation of drinking water on immune parameters in the intestine of homozygous mutant<br> Muc2 &minus;/&minus; , compared to Muc2 +/+ &nbsp;&nbsp;mice. To get into innate and adaptive immunity mechanisms of<br> gut inflammation, we tested Prkdc SCID Muc2 &minus;/&minus; &nbsp;&nbsp;strain, Muc2 knockout on SCID background, that<br> is characterized by lack of lymphocytes, in comparison with Prkdc SCID mice. We evaluated<br> intestinal cytokine profiling, macrophage and eosinophil infiltration, and expression of Nos2 and<br> Arg1 markers of macrophage activation in all strains. Markers of Th1, Treg and Th17 cells<br> (Tbx21, Foxp3, and Rorc expression) were evaluated in Muc2 &minus;/&minus; &nbsp;&nbsp;and Muc2 +/+ &nbsp;&nbsp;mice.<br> Both Muc2 &minus;/&minus; &nbsp;&nbsp;and Prkdc SCID Muc2 &minus;/&minus; &nbsp;&nbsp;mice demonstrated increased numbers of<br> macrophages, eosinophils, elevated levels of TNFa, GM-CSF, and IL-10 cytokines. In Muc2 &minus;/&minus; &nbsp;<br> mice we observed a wide range of pro-inflammatory cytokines elevated, such as IFN-gamma,<br> IL-1b, IL-12p70, IL-6, M-CSF, G-CSF, IL-17, MCP-1, RANTES, MIP1b, MIP2. Muc2 &minus;/&minus; &nbsp;&nbsp;mice<br> demonstrated increase of Nos2, Tbx21 and Foxp3 genes mRNA, while in Prkdc SCID Muc2 &minus;/&minus; &nbsp;&nbsp;mice<br> Arg1 expression was increased. We found that in Muc2 &minus;/&minus; &nbsp;mice L-fucose reduced macrophage<br> infiltration and IL-1a, TNFa, IFNgamma, IL-6, MCP-1, RANTES, MIP1b levels, decreased<br> Nos2 expression, and induced the expression of Treg marker Foxp3 gene. On the contrary, in<br> Prkdc SCID Muc2 &minus;/&minus; &nbsp;&nbsp;mice L-fucose had no effect on macrophage and eosinophil numbers, but<br> increased TNFa, GM-CSF, IL-12p70, IL-6, IL-15, IL-10, MCP1, G-CSF, IL-3 levels and Nos2<br> gene expression, and decreased Arg1 gene expression.<br> We demonstrated that anti-inflammatory effect of L-fucose observed in Muc2 &minus;/&minus; &nbsp;&nbsp;mice is<br> not reproduced in Prkdc SCID Muc2 &minus;/&minus; , which lack lymphocytes. We conclude that activation of<br> Treg cells is a key event that leads to resolution of inflammation upon L-fucose supplementation<br> in Muc2 &minus;/&minus; &nbsp;&nbsp;mice.</p>