Role of C3aR and C5aR in T_reg cells

Activation of the complement system is thought to be involved in the development of hypertension and target-organ damage. Now, Xiao-Hui Chen and colleagues report that complement 3a receptor (C3aR) and complement 5a receptor (C5aR) contribute to blood pressure regulation by modulating regulatory T (T_reg) cell functions.

In wild-type mice, the researchers show that angiotensin II (ANGII) infusion induced an increase in blood pressure, a decrease in the percentage of forkhead box protein P3 (FOXP3)⁺ T_reg cells in the kidneys and blood, and a significant upregulation of C3aR and C5aR expression in FOXP3⁺ T_reg cells. These effects were abrogated in mice with double knockout of C3aR and C5aR (DKO mice). ANGII-induced renal damage and vascular injury were also attenuated in DKO mice compared with wild-type controls; however, depletion of T_reg cells in DKO mice abolished these protective effects. By contrast, adoptive transfer of T_reg cells from DKO mice protected wild-type mice from ANGII-induced hypertension and target-organ damage.

In cultured CD4⁺CD25⁺ T_reg cells from wild-type mice, ANGII infusion induced an increase in the mRNA expression of C3aR and C5aR and a decrease in the expression of FOXP3. Stimulation with CD3 and CD28 antibodies also downregulated FOXP3 expression in T_reg cells from wild-type mice but not in those from DKO mice. In addition, the differentiation of DKO CD4⁺CD25⁻ T cells into FOXP3⁺ T_reg cells was increased in comparison to that of wild-type CD4⁺CD25⁻ T cells. Based on these data, the researchers suggest that double knockout of C3aR and C5aR enhances the functions of T_reg cells.

targeting C3aR and C5aR on T_reg cells could be a novel strategy for the treatment of hypertension

Finally, the researcher report that the serum levels of C3a and C5a as well as C5aR expression in FOXP3⁺ T_reg cells were increased in patients with hypertension compared with normotensive individuals. They conclude that “C3aR and C5aR play pivotal roles in [blood pressure] regulation and hypertension-related organ damage, likely through regulating T_reg cell functions,” and suggest that targeting C3aR and C5aR on T_reg cells could be a novel strategy for the treatment of hypertension.