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Interleukin17A Promotes Postoperative Cognitive Dysfunction by Triggering β-Amyloid Accumulation via the Transforming Growth Factor-β (TGFβ)/Smad Signaling Pathway.

Tian A, Ma H, Zhang R, Tan W, Wang X, Wu B, Wang J, Wan C - PLoS ONE (2015)

Bottom Line: We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1-42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus.Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1-42 accumulation in old subjects.These changes likely contribute to the cognitive decline seen in POCD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.

ABSTRACT
Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1-42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in Aβ1-42 and TGFβ/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGFβ/Smad activation and Aβ1-42 expression were reversed by IL17A receptor small interfering RNA and a TGFβ receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1-42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD.

No MeSH data available.


Related in: MedlinePlus

Glial fibrillary acidic protein (GFAP) expression in the hippocampus following hepatectomy in mice.Representative bands of the hippocampus illustrating expression of GFAP from control group at 1 day (C1), 3 days (C3), and 7 days (C7); from anesthesia group at 1 day (A1), 3 days (A3), and 7 days (A7); or from surgery plus anesthesia group at 1 day (SA1), 3 days (SA3), and 7 days (SA7). Data are represented as the mean ± SEM. *P<0.05; **P<0.01 vs. C group at the corresponding time point. #P<0.05; ##P<0.01 vs. A group at the corresponding time point. Groups were as follows: C, control; A, anesthesia; SA, surgery plus anesthesia (n = 8).
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pone.0141596.g004: Glial fibrillary acidic protein (GFAP) expression in the hippocampus following hepatectomy in mice.Representative bands of the hippocampus illustrating expression of GFAP from control group at 1 day (C1), 3 days (C3), and 7 days (C7); from anesthesia group at 1 day (A1), 3 days (A3), and 7 days (A7); or from surgery plus anesthesia group at 1 day (SA1), 3 days (SA3), and 7 days (SA7). Data are represented as the mean ± SEM. *P<0.05; **P<0.01 vs. C group at the corresponding time point. #P<0.05; ##P<0.01 vs. A group at the corresponding time point. Groups were as follows: C, control; A, anesthesia; SA, surgery plus anesthesia (n = 8).

Mentions: To determine if surgery induced IL17A-related cytokine production, hippocampal IL17A, IL6, and TGFβ mRNA levels were measured on postoperative days 1, 3, and 7. IL6 and TGFβ play critical roles in the development of the Th17 response and are positive regulators in the differentiation of Th17 cells. Anesthetics did not significantly increase IL17A, IL6, and TGFβ mRNA expression at any time point relative to controls (P>0.05). However, on postoperative day 1 and 3, the levels of IL17A, IL6, and TGFβ mRNA expression were elevated in group SA, peaking on day postoperative 3 (P<0.01). Likewise, protein expression of IL17A, IL6, and TGFβ was also markedly elevated on postoperative days 1 and 3 (day 1: P<0.05; day 3: P<0.01, Fig 3A–3C). GFAP is an often employed marker of astrocytic activation, an event which is thought to occur early during the formation of amyloid plaques [29]. Therefore, we investigated GFAP expression and found that hippocampal GFAP expression significantly increased on postoperative days 1 and 3 in group SA (day 1: P<0.05; day 3: P<0.01, Fig 4) and improved by postoperative day 7. We next measured APP and Aβ1–42 levels in order to investigate the effect of surgery on the production of Aβ. Hepatectomy was associated with an increase of APP and Aβ1–42 levels on postoperative day 1 and 3 (day 1: P<0.05; day 3: P<0.01, Fig 5A and 5B) and Aβ1–42 level up to postoperative day 7. The level on day seven was significantly higher than group C and group A (P<0.05). Immunohistochemistry was also used to detect Aβ1–42 expression, and similar results were obtained (Fig 6). Additionally, hepatectomy was associated with a significant increase in p Smad2/3 protein levels in the hippocampus relative to group C or group A on postoperative day 3 (P< 0.05, Fig 5C).


Interleukin17A Promotes Postoperative Cognitive Dysfunction by Triggering β-Amyloid Accumulation via the Transforming Growth Factor-β (TGFβ)/Smad Signaling Pathway.

Tian A, Ma H, Zhang R, Tan W, Wang X, Wu B, Wang J, Wan C - PLoS ONE (2015)

Glial fibrillary acidic protein (GFAP) expression in the hippocampus following hepatectomy in mice.Representative bands of the hippocampus illustrating expression of GFAP from control group at 1 day (C1), 3 days (C3), and 7 days (C7); from anesthesia group at 1 day (A1), 3 days (A3), and 7 days (A7); or from surgery plus anesthesia group at 1 day (SA1), 3 days (SA3), and 7 days (SA7). Data are represented as the mean ± SEM. *P<0.05; **P<0.01 vs. C group at the corresponding time point. #P<0.05; ##P<0.01 vs. A group at the corresponding time point. Groups were as follows: C, control; A, anesthesia; SA, surgery plus anesthesia (n = 8).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4624903&req=5

pone.0141596.g004: Glial fibrillary acidic protein (GFAP) expression in the hippocampus following hepatectomy in mice.Representative bands of the hippocampus illustrating expression of GFAP from control group at 1 day (C1), 3 days (C3), and 7 days (C7); from anesthesia group at 1 day (A1), 3 days (A3), and 7 days (A7); or from surgery plus anesthesia group at 1 day (SA1), 3 days (SA3), and 7 days (SA7). Data are represented as the mean ± SEM. *P<0.05; **P<0.01 vs. C group at the corresponding time point. #P<0.05; ##P<0.01 vs. A group at the corresponding time point. Groups were as follows: C, control; A, anesthesia; SA, surgery plus anesthesia (n = 8).
Mentions: To determine if surgery induced IL17A-related cytokine production, hippocampal IL17A, IL6, and TGFβ mRNA levels were measured on postoperative days 1, 3, and 7. IL6 and TGFβ play critical roles in the development of the Th17 response and are positive regulators in the differentiation of Th17 cells. Anesthetics did not significantly increase IL17A, IL6, and TGFβ mRNA expression at any time point relative to controls (P>0.05). However, on postoperative day 1 and 3, the levels of IL17A, IL6, and TGFβ mRNA expression were elevated in group SA, peaking on day postoperative 3 (P<0.01). Likewise, protein expression of IL17A, IL6, and TGFβ was also markedly elevated on postoperative days 1 and 3 (day 1: P<0.05; day 3: P<0.01, Fig 3A–3C). GFAP is an often employed marker of astrocytic activation, an event which is thought to occur early during the formation of amyloid plaques [29]. Therefore, we investigated GFAP expression and found that hippocampal GFAP expression significantly increased on postoperative days 1 and 3 in group SA (day 1: P<0.05; day 3: P<0.01, Fig 4) and improved by postoperative day 7. We next measured APP and Aβ1–42 levels in order to investigate the effect of surgery on the production of Aβ. Hepatectomy was associated with an increase of APP and Aβ1–42 levels on postoperative day 1 and 3 (day 1: P<0.05; day 3: P<0.01, Fig 5A and 5B) and Aβ1–42 level up to postoperative day 7. The level on day seven was significantly higher than group C and group A (P<0.05). Immunohistochemistry was also used to detect Aβ1–42 expression, and similar results were obtained (Fig 6). Additionally, hepatectomy was associated with a significant increase in p Smad2/3 protein levels in the hippocampus relative to group C or group A on postoperative day 3 (P< 0.05, Fig 5C).

Bottom Line: We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1-42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus.Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1-42 accumulation in old subjects.These changes likely contribute to the cognitive decline seen in POCD.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, the first Affiliated Hospital of China Medical University, Nanjing North Street 155, Shenyang, Liaoning, China.

ABSTRACT
Although postoperative cognitive dysfunction (POCD) is relatively common in elderly patients who have undergone major surgery, the mechanisms underlying this postoperative complication are unclear. Previously, we have investigated the role of cytokine-mediated hippocampal inflammation in the development of POCD in a rat model. Here, we sought to determine in mice the role of cytokine interleukin17A (IL17A) in POCD and to characterize the associated signaling pathways. Old mice underwent hepatectomy surgery in the presence or absence of IL17A monoclonal antibody, and cognitive function, hippocampal neuroinflammation, and pathologic markers of Alzheimer's disease (AD) were assessed. We found that the level of IL17A in the hippocampus was increased in hepatectomy mice and that cognitive impairment after surgery was associated with the appearance of certain pathological hallmarks of AD: activation of astrocytes, β-amyloid1-42 (Aβ1-42) production, upregulation of transforming growth factor-β (TGFβ), and increased phosphorylation of signaling mother against decapentaplegic peptide 3 (Smad3) protein in the hippocampus. Surgery-induced changes in cognitive dysfunction and changes in Aβ1-42 and TGFβ/Smad signaling were prevented by the administration of IL17A monoclonal antibody. In addition, IL17A-stimulated TGFβ/Smad activation and Aβ1-42 expression were reversed by IL17A receptor small interfering RNA and a TGFβ receptor inhibitor in cultured astrocytes. Our findings suggest that surgery can provoke IL17A-related hippocampal damage, as characterized by activation of astrocytes and TGFβ/Smad pathway dependent Aβ1-42 accumulation in old subjects. These changes likely contribute to the cognitive decline seen in POCD.

No MeSH data available.


Related in: MedlinePlus