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LETTERS TO THE EDITOR |
Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada
There has been a recent surge of interest in the literature for the anaphylatoxins C3a and C5a and their role in inflammatory diseases. While knockout studies have provided important information regarding the role of C3a in allergic diseases such as asthma (1, 2), the publication of a potent small molecule antagonist of the C3a receptor, SB 290157, offered the possibility of confirming C3a-specific events in animal models of disease without the provisos normally associated with genetically modified organisms (3). Indeed, a number of studies have recently taken advantage of the availability of SB 290157 to ascribe roles to C3a, or refute such roles, in a variety of disease models (4, 5, 6, 7, 8). One case in point is the recent article in The Journal of Immunology by Baelder et al. (4) showing that C3a does not have an important role in the pathogenesis of airway hyperreactivity (AHR) in a murine allergen-induced model of asthma. The findings presented in that study, based on the lack of an SB 290157-dependent effect on AHR, contradict previous observations in C3aR-knockout mice (1, 2). Interestingly, not only did SB 290157 fail to protect mice against allergen-induced AHR, but the authors also observed an SB 290157-dependent increase in AHR in the context of C5aR blockade.
Our group has recently obtained data explaining this discrepancy and cautioning against the use of SB 290157 as a tool to investigate C3a-related effects (9). Indeed, while SB 290157 acts as an antagonist in a cellular system where receptor density is low, the compound is a full agonist of C3aR in cell lines that express higher levels of C3aR, consistent with SB 290157 being a partial agonist of C3aR. Since C3aR levels are increased in smooth muscle cells in an allergen-challenge model of asthma (10), the possibility exists that SB 290157 can activate, rather than antagonize, C3aR in the model used by Baelder et al. A role of C3a in AHR should therefore not be discounted based on the findings in the otherwise important study by Baelder and colleagues.
References
Division of Molecular Immunology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229
The findings by Mathieu et al. (R1 ) demonstrate that SB 290157 can act as a C3aR agonist as well as a C3aR antagonist. Importantly, antagonistic properties have been found with C3aR-transfected cells and cell lines, whereas agonistic behavior was demonstrated with primary cells. These data provide an interesting alternative explanation for our observation that administration of SB 290157 1) had no effect on AHR and 2) reduced the inhibitory effect of C5aR blockade on AHR development (R2 ). However, the lack of data on agonistic properties of SB 290157 on primary cells confines the data by Mathieu et al. Clearly, SB 290157 exhibited antagonistic properties in our model, as evidenced by reduced neutrophilic and eosinophilic inflammation as well as reduced IL-4 and IL-6 in BAL.
The missing effect of C3aR blockade on AHR is not necessarily contradictory to the data obtained with C3aR-deficient mice (R3 ). In our study, C3aR blockade was effective only during the effector phase but not during allergen priming. In line with data by Drouin et al. (R3 ) and Kawamoto et al. (R4 ), C3a may impact Th2 development at the dendritic cell/T cell interphase, something that was not affected by our treatment. Further, administration of SB 290157 may promote activation of another receptor for C3a/C3adesArg, C5L2, something that may antagonize the inhibitory effect of C5aR blockade on AHR. In support of this view, C5L2 was found to function not solely as a decoy receptor for C5a/C5adesArg but as a signaling receptor in response to C3a/C3adesArg (R5 ).
References
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  J Mocco, W. J. Mack, A. F. Ducruet, S. A. Sosunov, M. E. Sughrue, B. G. Hassid, M. N. Nair, I. Laufer, R. J. Komotar, M. Claire, et al. Complement Component C3 Mediates Inflammatory Injury Following Focal Cerebral Ischemia Circ. Res., July 21, 2006; 99(2): 209 - 217. [Abstract] [Full Text] [PDF]
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