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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
PPARβ/δ activation of CD300a controls intestinal immunity
Toshiya Tanaka1, Satoko Tahara-Hanaoka2, Tsukasa Nabekura2
1Laboratory for Systems Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), The University of Tokyo, Tokyo 153-8904, Japan.
Abstract:
Macrophages are important for maintaining intestinal immune homeostasis. Here, we show that PPARβ/δ (peroxisome proliferator-activated receptor β/δ) directly regulates CD300a in macrophages that express the immunoreceptor tyrosine based-inhibitory motif (ITIM)-containing receptor. In mice lacking CD300a, high-fat diet (HFD) causes chronic intestinal inflammation with low numbers of intestinal lymph capillaries and dramatically expanded mesenteric lymph nodes. As a result, these mice exhibit triglyceride malabsorption and reduced body weight gain on HFD. Peritoneal macrophages from Cd300a-/- mice on HFD are classically M1 activated. Activation of toll-like receptor 4 (TLR4)/MyD88 signaling by lipopolysaccharide (LPS) results in prolonged IL-6 secretion in Cd300a-/- macrophages. Bone marrow transplantation confirmed that the phenotype originates from CD300a deficiency in leucocytes. These results identify CD300a-mediated inhibitory signaling in macrophages as a critical regulator of intestinal immune homeostasis.
Insights
CD300a deficiency in macrophages disrupts intestinal immune homeostasis, leading to inflammation and malabsorption, particularly on a high-fat diet. This highlights CD300a
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Macrophages play a crucial role in maintaining intestinal immune balance.
- Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) influences immune responses.
- CD300a is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor on immune cells.
Purpose of the Study:
- To investigate the role of PPARβ/δ in regulating CD300a expression in macrophages.
- To determine the impact of CD300a deficiency on intestinal immunity and metabolism under high-fat diet conditions.
Main Methods:
- Utilized knockout mouse models lacking CD300a.
- Administered high-fat diet (HFD) to assess metabolic and inflammatory responses.
- Performed bone marrow transplantation to confirm the cellular origin of observed phenotypes.
- Analyzed macrophage activation states (M1) and cytokine secretion (IL-6) following TLR4/MyD88 pathway stimulation.
Main Results:
- CD300a deficiency in mice on HFD resulted in chronic intestinal inflammation, reduced lymph capillaries, and enlarged mesenteric lymph nodes.
- Mice lacking CD300a exhibited triglyceride malabsorption and impaired weight gain on HFD.
- Macrophages from CD300a-deficient mice showed enhanced M1 activation and prolonged IL-6 secretion upon LPS stimulation.
- Phenotypic changes were attributed to CD300a deficiency in leukocytes.
Conclusions:
- PPARβ/δ directly regulates CD300a in macrophages.
- CD300a-mediated inhibitory signaling is critical for regulating intestinal immune homeostasis.
- CD300a deficiency exacerbates diet-induced intestinal inflammation and metabolic dysfunction.
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