Key result
mPGES-1 or EP4 deficiency impairs hindlimb ischaemia recovery in mice by reducing Treg accumulation.
Why the study?
Although mPGES-1/PGE2 induces angiogenesis and PGE2 modulates regulatory T cells (Tregs), which are implicated in angiogenesis, the hypothesis that mPGES-1/PGE2-EP signalling promotes ischaemic recovery via Treg accumulation required testing.
Does the mPGES-1/PGE2-EP4 axis promote recovery from ischaemia via recruitment of regulatory T cells in a mouse model of hindlimb ischaemia?
Does the mPGES-1/PGE2-EP4 axis promote recovery from ischaemia via recruitment of regulatory T cells in a mouse model of hindlimb ischaemia?
The mPGES-1/PGE2 axis promotes neovascularization and recovery from ischaemia via the EP4 receptor by recruiting regulatory T cells, suggesting EP4 agonists as potential treatments for peripheral artery disease.
Supports mPGES-1/EP4 axis in mouse ischemic recovery via regulatory T cells; hypothesis-generating for EP4 agonists in peripheral artery disease.
AIMS: Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1-4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-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 (FoxP3)+ cells in ischaemic muscle tissue was decreased in mPges-1-/- mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) 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-β 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/PGE2 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.
No takes yet. Share an insight, caveat, or question.
Amano et al. (2022) studied Hindlimb ischaemia. mPGES-1 or EP4 receptor deficiency vs. Wild-type mice was evaluated on Recovery from ischaemia and accumulation of FoxP3+ cells. Deficiency of mPGES-1 or EP4 receptor suppressed recovery from hindlimb ischaemia and decreased the accumulation of regulatory T cells in ischaemic muscle tissue compared with wild-type mice.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: