The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity

Abstract

Complement activation generates the core effector protein C5a, a potent immune molecule that is linked to multiple inflammatory diseases. Two C5a receptors, C5aR1 (C5aR, CD88) and C5aR2 (C5L2, GPR77), mediate the biological activities of C5a. Although C5aR1 has broadly acknowledged proinflammatory roles, C5aR2 remains at the center of controversy, with existing findings supporting both immune-activating and immune-dampening functions. Recent progress has been made toward resolving these issues. Instead of being a pure recycler and sequester of C5a, C5aR2 is capable of mediating its own set of signaling events and through these events exerting significant immunomodulatory effects not only toward C5aR1 but also other pattern recognition receptors and innate immune systems, such as NLRP3 inflammasomes. This review highlights the existing knowns and unknowns concerning C5aR2 and provides a timely update on recent breakthroughs which are expected to have a substantial impact on future fundamental and translational C5aR2 research.

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

“…[6] C5aR2 is present upon adipocytes, monocytes, select T-cell populations, fibroblasts and mast cells, which suggests that antagonism of the C5aR1 only may not eliminate all downstream functions of C5a. [10] It should be noted, however, that the specific actions of C5aR2 have been described only in vitro and in vivo verification in humans is lacking. [9] It is likely that C5aR2 has anti-inflammatory functions during periods of acute inflammation as a mechanism for limiting tissue damage; however, its intracellular actions can also promote inflammation in the setting of chronic inflammation to facilitate response to microbial insults.…”

“…[7,8] There has been much controversy in the literature regarding whether C5aR2 is a pure recycler and sequesterer of C5a, or whether it has other pro-inflammatory and regulatory functions. [9,10] There are moves to develop more robust animal models consistent with human expression of C5a receptors given that the sole animal model (floxed tandem dye Tomato-C5aR2 knock-in mouse) [11] has significant variation in the expression of C5a receptors on T cells compared with humans. [10] It should be noted, however, that the specific actions of C5aR2 have been described only in vitro and in vivo verification in humans is lacking.…”

“…[42,43] These pathogens-derived proteases can also cleave cell-surface receptors such as CD14, resulting in impaired clearance of apoptotic cells and promotion of chronic inflammation. [10] Examining the patterns of complement activation in HS lesions may be informative in determining the contribution of the cutaneous microbiome to inflammatory drive in HS. [10] Examining the patterns of complement activation in HS lesions may be informative in determining the contribution of the cutaneous microbiome to inflammatory drive in HS.…”

“…C3 and ASP levels are also seen elevated in non-obese PCOS patients and are decreased by the use of metformin. [10,15] Given these findings, if complement were a major driver of HS pathogenesis, the association between HS and metabolic comorbidities would be expected to be much greater than observed. [50] The downstream effects of C5aR2 activation are dependent upon the background inflammatory milieu, and however, in the setting of chronic inflammation, C5aR1 surface expression is upregulated leading to further pro-inflammatory effects including further production and release of complement proteins in the systemic circulation.…”

Pressure Cycling Technology Assisted Mass Spectrometric Quantification of Gingival Tissue Reveals Proteome Dynamics during the Initiation and Progression of Inflammatory Periodontal Disease

“…The complement anaphylatoxin C5a is a proinflammatory component of host defense that functions through two identified receptors, C5a receptor 1 (C5aR1) and C5aR2, also known as C5L2 . C5L2 is a regulator of C5aR1‐mediated signal transduction but also has immunomodulatory action on TLRs and the NLRP3 inflammasome …”