The microsomal prostaglandin E synthase-1/prostaglandin E2 axis induces recovery from ischaemia via recruitment of regulatory T cells

被引：7

作者：

Amano, Hideki ^{[1
]}

Eshima, Koji ^{[2
]}

Ito, Yoshiya ^{[1
]}

Nakamura, Masaki ^{[3
]}

Kitasato, Hidero ^{[3
]}

Ogawa, Fumihiro ^{[1
]}

Hosono, Kanako ^{[1
]}

Iwabuchi, Kazuya ^{[2
]}

Uematsu, Satoshi ^{[4
]}

Akira, Shizuo ^{[5
]}

Narumiya, Shuh ^{[6
]}

Majima, Masataka ^{[1
,7
]}

机构：

[1] Kitasato Univ, Dept Pharmacol, Sch Med, Minami Ku, 1-15-1 Kitasato, Sagamihara, Kanagawa 2520373, Japan

[2] Kitasato Univ, Dept Immunol, Sch Med, Sagamihara, Kanagawa, Japan

[3] Kitasato Univ, Dept Microbiol, Sch Allied Hlth Sci, Sagamihara, Kanagawa, Japan

[4] Osaka City Univ, Dept Immunol & Genom, Grad Sch Med, Osaka, Japan

[5] Osaka Univ, WPI Immunol Frontier Res Ctr IFReC, Lab Host Def, Osaka, Japan

[6] Kyoto Univ, Dept Drug Discovery Med, Grad Sch Med, Kyoto, Japan

[7] Kanagawa Inst Technol, Dept Med Therapeut, Atsugi, Kanagawa, Japan

来源：

CARDIOVASCULAR RESEARCH | 2023年 / 119卷 / 05期

关键词：

mPGES-1; EP4; Tregs; Angiogenesis; TGF-beta; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; BLOOD-FLOW RECOVERY; HINDLIMB ISCHEMIA; ARTERIOGENIC RESPONSE; IMMUNE-RESPONSES; PROGENITOR CELLS; SELF-TOLERANCE; E SYNTHASE-1; ANGIOGENESIS; CD4(+);

D O I：

10.1093/cvr/cvac137

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E-2 (PGE(2)) induces angiogenesis through the prostaglandin E-2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE(2) is known to modulate function and differentiation of Tregs. We hypothesized that mPGES-1/PGE(2)-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs. Methods and results Wild-type (WT), mPGES-1-deficient (mPges-1(-/-)), and EP4 receptor-deficient (Ep4(-/-)) male mice 6-8 weeks old were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1(-/-) mice and compared with WT mice. The number of accumulated forkhead box protein P3 (Fox P3)(+) cells in ischaemic muscle tissue was decreased in mPges-1(-/-) mice compared with that in WT mice. Expression levels of transforming growth factor-beta (TGF-beta) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1(-/-) mice. The number of accumulated FoxP3(+) cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1(-/-) mice. Recovery from ischaemia was significantly suppressed in Ep4(-/-) mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-beta were suppressed in Ep4(-/-) mice. Moreover, the number of accumulated FoxP3(+) cells in ischaemic tissue was diminished in Ep4(-/-) mice compared with that in Ep4(+/+) mice. Conclusion These findings suggested that mPGES-1/PGE(2) induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease. [GRAPHICS] .

引用

页码：1218 / 1233

页数：16

共 55 条

[31] FOXP3+ regulatory T cells: control of FOXP3 expression by pharmacological agents [J].