The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist

Area of Science:

• Immunology
• Pharmacology
• Cell Biology

Background:

• Complement activation generates anaphylatoxins C3a and C5a, which signal through C3aR, C5aR1, and C5aR2.
• SB290157, an early C3aR antagonist, exhibits non-selective and context-dependent activities.
• Despite concerns, SB290157 remains widely used for C3aR research.

Purpose of the Study:

• To investigate the pharmacological selectivity of SB290157 across human anaphylatoxin receptors.
• To clarify the dual activity of SB290157 on C3aR and its off-target effects.

Main Methods:

• Screening SB290157 against C3aR, C5aR1, and C5aR2 in cell models.
• Assessing beta-arrestin recruitment and ERK signaling in primary macrophages.
• Evaluating SB290157's activity in both transfected cells and primary immune cells.

Main Results:

• SB290157 acts as a partial agonist at C5aR2, inducing beta-arrestin recruitment and dampening C5a-induced ERK signaling in macrophages.
• SB290157 functions as a potent agonist at human C3aR in transfected cells but as an antagonist in primary human macrophages.
• Off-target effects at C5aR2 may contribute to observed functions attributed to C3aR modulation.

Conclusions:

• SB290157 exhibits complex and non-selective pharmacology, acting as both an agonist and antagonist depending on the receptor and cell type.
• The study strongly cautions against the use of SB290157 as a specific research tool for C3aR.
• Potential off-target activities, particularly at C5aR2, must be considered when interpreting data from studies using SB290157.