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The dual role of scavenger receptor class A in development of diabetes in autoimmune NOD mice.

Shimizu M, Yasuda H, Hara K, Takahashi K, Nagata M, Yokono K - PLoS ONE (2014)

Bottom Line: These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects.These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection.Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of General Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.

ABSTRACT
Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic β cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A) may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A-/- nonobese diabetic (NOD) mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A-/- NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I:C)) was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I:C). In addition, injection of high-dose poly(I: C) to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A-/- NOD mice compared with untreated SR-A-/- NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A-/- NOD mice treated with poly(I:C) than in untreated SR-A-/- NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A-/- NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I:C) treatment even in SR-A-/- NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.

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Hypothesized TLR3 RNA-sensing system.(A) Extracellular dsRNA binds SR-A or raftlin on cell surface and enters via endocytosis. (B) SR-A communicates a negative signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (C) Raftlin communicates a positive signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (D) dsRNA escapes the endosome and is detected in the cytoplasm by MDA5 and/or RIG-I, which induces IFN-β production via IPS-1 without TLR3 signaling.
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pone-0109531-g010: Hypothesized TLR3 RNA-sensing system.(A) Extracellular dsRNA binds SR-A or raftlin on cell surface and enters via endocytosis. (B) SR-A communicates a negative signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (C) Raftlin communicates a positive signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (D) dsRNA escapes the endosome and is detected in the cytoplasm by MDA5 and/or RIG-I, which induces IFN-β production via IPS-1 without TLR3 signaling.

Mentions: Interestingly, a more recent study showed that raftlin is another cell surface receptor for RNA and that raftlin-mediated endocytosis is important for the TLR3 RNA-sensing system [46]. A previous study reported that EAE was ameliorated and IL-17 production reduced in raftlin−/− mice [47]. Taking these findings together with our study, we hypothesize that there are three pathways for dsRNA signaling as shown in Figure 10. Extracellular dsRNA binds SR-A or raftlin on the cell surface and enters via endocytosis. SR-A communicates a negative signal to endosomal TLR3 and raftlin communicates a positive signal to endosomal TLR3, which induces TNF-α production via TRIF [11]. dsRNA escapes the endosome and is detected in the cytoplasm by MDA5 and/or RIG-I, which induces IFN-β production via IPS-1 without signaling TLR3 [48]. We speculate that if a negative signal cannot be conveyed from SR-A to TLR3, TNF-α production might be increased through the raftlin-mediated TLR3 signaling pathway, and that this might be involved in the acceleration of T1D development in young SR-A−/− NOD mice treated with poly(I∶C). In an infection, we consider that the balance between the SR-A signal and the raftlin signal might play a crucial role in diabetes progression and that strong stimulation might lead to an increase in the raftlin signal, resulting in the acceleration of T1D development. Thus, SR-A may play an unfavorable role in steady-state conditions and a protective role in a mild infection.


The dual role of scavenger receptor class A in development of diabetes in autoimmune NOD mice.

Shimizu M, Yasuda H, Hara K, Takahashi K, Nagata M, Yokono K - PLoS ONE (2014)

Hypothesized TLR3 RNA-sensing system.(A) Extracellular dsRNA binds SR-A or raftlin on cell surface and enters via endocytosis. (B) SR-A communicates a negative signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (C) Raftlin communicates a positive signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (D) dsRNA escapes the endosome and is detected in the cytoplasm by MDA5 and/or RIG-I, which induces IFN-β production via IPS-1 without TLR3 signaling.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4208757&req=5

pone-0109531-g010: Hypothesized TLR3 RNA-sensing system.(A) Extracellular dsRNA binds SR-A or raftlin on cell surface and enters via endocytosis. (B) SR-A communicates a negative signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (C) Raftlin communicates a positive signal to endosomal TLR3, which binds dsRNA and induces TNF-α production via TRIF. (D) dsRNA escapes the endosome and is detected in the cytoplasm by MDA5 and/or RIG-I, which induces IFN-β production via IPS-1 without TLR3 signaling.
Mentions: Interestingly, a more recent study showed that raftlin is another cell surface receptor for RNA and that raftlin-mediated endocytosis is important for the TLR3 RNA-sensing system [46]. A previous study reported that EAE was ameliorated and IL-17 production reduced in raftlin−/− mice [47]. Taking these findings together with our study, we hypothesize that there are three pathways for dsRNA signaling as shown in Figure 10. Extracellular dsRNA binds SR-A or raftlin on the cell surface and enters via endocytosis. SR-A communicates a negative signal to endosomal TLR3 and raftlin communicates a positive signal to endosomal TLR3, which induces TNF-α production via TRIF [11]. dsRNA escapes the endosome and is detected in the cytoplasm by MDA5 and/or RIG-I, which induces IFN-β production via IPS-1 without signaling TLR3 [48]. We speculate that if a negative signal cannot be conveyed from SR-A to TLR3, TNF-α production might be increased through the raftlin-mediated TLR3 signaling pathway, and that this might be involved in the acceleration of T1D development in young SR-A−/− NOD mice treated with poly(I∶C). In an infection, we consider that the balance between the SR-A signal and the raftlin signal might play a crucial role in diabetes progression and that strong stimulation might lead to an increase in the raftlin signal, resulting in the acceleration of T1D development. Thus, SR-A may play an unfavorable role in steady-state conditions and a protective role in a mild infection.

Bottom Line: These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects.These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection.Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of General Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.

ABSTRACT
Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic β cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A) may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A-/- nonobese diabetic (NOD) mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A-/- NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I:C)) was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I:C). In addition, injection of high-dose poly(I: C) to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A-/- NOD mice compared with untreated SR-A-/- NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A-/- NOD mice treated with poly(I:C) than in untreated SR-A-/- NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A-/- NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I:C) treatment even in SR-A-/- NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.

Show MeSH
Related in: MedlinePlus