A Commentary On: “NFκB-Activated Astroglial Release of Complement C3 Compromises Neuronal Morphology and Function Associated with Alzheimer’s Disease”. A cautionary note regarding C3aR

GENERAL COMMENTARY published: 07 May 2015 doi: 10.3389/fimmu.2015. 00220 A commentary on: “NF κ B-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease”. A cautionary note regarding C3aR Trent M. Woodruff 1 * and Andrea J. Tenner 2 School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia, 2 Department of Molecular Biology and Biochemistry, Institute for Memory Impairment and Neurological Disorders, University of California-Irvine, Irvine, CA, USA Keywords: complement, C3aR, Alzheimer’s disease, SB290157 A commentary on Edited by: Peter F. Zipfel, Leibniz Institute for Natural Product Research and Infection Biology, Germany Reviewed by: Daniel Ricklin, University of Pennsylvania, USA Josh Thurman, University of Colorado, USA *Correspondence: Trent M. Woodruff t.woodruff@uq.edu. au Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology Received: 30 March 2015 Accepted: 23 April 2015 Published: 07 May 2015 Citation: Woodruff TM and Tenner AJ (2015) A commentary on: “NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease”. A cautionary note regarding C3aR. Front. Immunol. 6:220. doi: 10.3389/fimmu.2015. 00220 NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease by Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, et al. Neuron (2015) 85:101–15. doi: 10.1016/j.neuron. 2014.11. 018 Introduction A recent study by Zheng and colleagues in Neuron (1) shows convincing evidence that activation of NF-κB in astrocytes induces expression of the complement component 3 (C3) and impairs neuronal function [summarized by Yates (2)]. The authors also state that the detrimental effects of astrocyte- derived C3 are due to the interaction of the C3 cleavage fragment, C3a, with its receptor (C3aR) on neurons (although no evidence of neuronal C3aR expression, nor generation of the cleavage product C3a, was provided). There are a number of caveats with this latter interpretation due to the use of the so-called C3aR-antagonist SB290157 (3), upon which they base this conclusion. These are summarized below. Off-Target Activity In 2004, Proctor and colleagues (4) reported that when SB290157 was administered to rats (at the same dose as used by Zheng and colleagues), it caused rapid neutropenia. Although SB290157 could block ischemia-induced intestinal pathology in rats, this therapeutic effect was shown not to be due to inhibition of the C3aR, but rather, due to the non-specific effect on circulating leukocyte concentrations (4). This finding was later replicated in mice by an independent group (5). These authors summarized that “C3aR antagonism does not appear to be responsible for the anti-inflammatory actions of this C3aRA” (4). Agonist Versus Antagonist Activity In 2005, Mathieu and colleagues (6) reported that SB290157 surprisingly had full agonist (not antagonist) activity at C3aR in many cell systems. They found that SB290157 completely activated Frontiers in Immunology | www.frontiersin. org May 2015 | Volume 6 | Article 220