An unexpected role for the anaphylatoxin C5a receptor in allergic sensitization

Lambrecht, Bart N.

doi:10.1172/jci27876

Cited by 25 publications

(11 citation statements)

References 45 publications

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“…These anaphylatoxins can induce ASM contraction [20, 58, 59], mucus secretion [60, 61], increased microvascular permeability [62, 63] [17, 24], vasodilation [64, 65], leukocyte migration and activation, and degranulation of mast cells [66], which are the hallmarks features of asthma. Further, the most important, neutralization of anaphylatoxin activity through the use of blocking antibodies, genetic targeting or by using specific antagonist of various complement factors or their receptors has been shown to attenuate allergic inflammation, and AHR in mice, and guinea pigs [67, 68]. It is becoming increasingly clear that immunoregulatory events occurring at the interface of innate and adaptive immunity play an important role in asthma pathogenesis [13].…”

Section: Discussionmentioning

confidence: 99%

Complement components as potential therapeutic targets for asthma treatment

Khan

Nicolls

Surguladze³

et al. 2014

Respiratory Medicine

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Summary Asthma is the most common respiratory disorder, and is characterized by distal airway inflammation and hyperresponsiveness. This disease challenges human health because of its increasing prevalence, severity, morbidity, and the lack of a proper and complete cure. Asthma is characterized by TH2–skewed inflammation with elevated pulmonary levels of IL-4, IL-5, and IL-13 levels. Although there are early forays into targeting TH2 immunity, less-specific corticosteroid therapy remains the immunomodulator of choice. Innate immune injury mediated by complement components also act as potent mediators of the allergic inflammatory responses and offer a new and exciting possibility for asthma immunotherapy. The complement cascade consists of a number of plasma- and membrane-bound proteins, and the cleavage products of these proteins (C3 and C5) regulate the magnitude of adaptive immune responses. Complement protein are responsible for many pathophysiological features of asthma, including inflammatory cell infiltration, mucus secretion, increases in vascular permeability, and smooth muscle cell contraction. This review highlights the complement-mediated injury during asthma inflammation, and how blockade of active complement mediators may have therapeutic application.

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Section: Discussionmentioning

confidence: 99%

Complement components as potential therapeutic targets for asthma treatment

Khan

Nicolls

Surguladze³

et al. 2014

Respiratory Medicine

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“…C5a has been implicated in many diseases, such as sepsis (37), rheumatoid arthritis (38), asthma and allergy (36, 39–41), ischemia‐reperfusion injuries (42–44), inflammatory bowel disease (45–47), atherosclerosis (48), and neurodegeneration (16, 49–51). However, many of these studies have focused on C5aR without specifically investigating the role of C5L2.…”

Section: C5l2 Physiology and Pathophysiologymentioning

confidence: 99%

C5L2: a controversial receptor of complement anaphylatoxin, C5a

Li¹,

Coulthard²,

Wu³

et al. 2012

FASEB j.

181

158

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C5a is the paramount proinflammatory mediator of the complement cascade, and has been previously thought to act only through a single, G-protein-coupled, C5a receptor (C5aR; also termed CD88). In 2000, a second C5a receptor, C5L2 (previously known as GPR77), was discovered; yet, despite 12 yr of intensive research, its biological, or pathophysiological, function is both enigmatic and controversial. Unlike C5aR, this receptor does not couple to G proteins, and early studies promoted the hypothesis that C5L2 functions as a decoy receptor. However, recent data have provided other evidence for more complicated and conflicting interactions between C5L2 and other inflammatory mediators. C5L2 has been recently demonstrated to physically interact with both C5aR and β-arrestin to negatively regulate C5aR signaling toward an anti-inflammatory manner, and to reduce pathology, in several disease models in vivo. In direct contrast, other groups have demonstrated that C5L2 stimulation caused release of HMGB1 both in vitro and in vivo, and enhanced pathology in sepsis models, suggesting a clear proinflammatory signaling role. These astoundingly contradictory data challenge our precepts and complicate the foundational bases for the possible targeting of C5L2 as a therapeutic option in inflammatory disease. C5L2 may be the great masquerader in complement biology; its function dependent on the cell type, species, and disease context. Because of these unusual and unforeseen complexities, we present the current state of knowledge on C5L2 structure, expression and, most controversially, its putative functions.-Li, R., Coulthard, L.G., Wu, M. C. L., Taylor, S. M., Woodruff, T. M. C5L2: a controversial receptor of complement anaphylatoxin, C5a.

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“…The anaphylatoxins (ATs) C3a and C5a are generated following complement activation and are recognized as proinflammatory mediators of allergic asthma. However, recent studies suggest an unexpected immunoregulatory role for C5a during allergen sensitization (3,4). C5a exerts its effects mainly through binding to the C5a receptor (C5aR) that is widely expressed (2).…”

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confidence: 99%