Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

Abstract

The complement activation product C3a is often described as a proinflammatory mediator, alongside its downstream cousin, C5a. However, emerging studies show that C3a has several anti-inflammatory facets in vivo. For example, in the acute inflammatory response, C3a acts in direct opposition to C5a, through preventing the accumulation of neutrophils in inflamed tissues by independently regulating their mobilization. This acute, protective, and opposing activity of C3a to C5a is also illustrated in models of septicemia. In this article, we reinvestigate the discovery and original classification of C3a as a proinflammatory mediator and highlight the emerging studies demonstrating anti-inflammatory effects for C3a in the immune response. It is our hope that this review illuminates these apparently contradictory roles for C3a and challenges the general dogma surrounding C3a, which, historically, has ubiquitously been described as a proinflammatory mediator. In light of this, we urge investigators to use “inflammatory modulator” as the descriptor for C3a.

Radiotherapy: killing with complement

“…Thus, future studies should examine the role of each specific anaphylatoxin and the additional receptor, C5a2R. This is particularly important as C3a and C5a have opposing actions in multiple diseases including asthma, lupus, and septic shock where C5a is pro-inflammatory and C3a is anti-inflammatory (20). The C3a-C5a dichotomy may also be due to possible interactions of either C5a or C3a with C5a2R.…”

The anaphylatoxin receptors in neural progenitor physiology

“…Additionally, even within its roles in immunity there is debate as to whether the receptor operates, in an overarching manner, to promote or inhibit inflammation 138 . C3aR offers a promising target for modulation in pathologies, especially given its 'bilingualism' in the context of inflammation.…”

Contribution of complement anaphylatoxin receptors to melanoma growth: potential therapeutic targets

“…C3a consists of 77 amino acids, and has 36% overall homology to the C5a sequence, with higher homology in the C-terminal "active" region of the molecule (Takabayashi et al, 1996). It exerts its main biological effects by binding to a single receptor, C3aR, although other receptors and functions for C3a have been identified (Coulthard and Woodruff, 2015).…”

“…In addition to C5a, complement activation leads to the production of another peptide, C3a, which is less well studied, but generally thought to have similar effects (Klos et al, 2013). This simplistic view of C3a however has been challenged recently (Coulthard and Woodruff, 2015).…”