Monitoring C3aR Expression Using a Floxed tdTomato-C3aR Reporter Knock-in Mouse

Quell, Katharina M.; Karsten, Christian M.; Kordowski, Anna; Almeida, Larissa Nogueira; Briukhovetska, Daria; Wiese, Anna V.; Sun, Jing; Ender, Fanny; Antoniou, Konstantina; Schröder, Torsten; Schmudde, Inken; Berger, Johann L.; König, Peter; Vollbrandt, Tillman; Laumonnier, Yves; Köhl, Jörg

doi:10.4049/jimmunol.1700318

Cited by 60 publications

(72 citation statements)

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“…Although mouse neutrophils have been suggested to express C3aR [28,38], recent evidence shows that mouse neutrophilsin contrast to human neutrophils [64] do not express C3aR [65]. This would explain the lack of a C3aR-dependent phenotype in the mouse whole blood model.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

et al. 2019

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The complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar −/mice, whereas C5ar1 −/and C5ar2 −/mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1 −/mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8 Δ71−73) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a "super-agonist" peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis.

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Section: Discussionmentioning

confidence: 99%

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

et al. 2019

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“…First, we could not exclude the possibility that the therapeutic effects of C3aRa were partially due to its systemic effects as macrophages, which also expressed C3aR [50], are recruited into the hippocampus after surgery to exacerbate neuroinflammation and cognitive dysfunction [5, 36]. Second, further studies are needed to understand the neuro-glia crosstalk in this model and the contribution of astrocytic C3-microglial C3aR signaling on synaptic pruning and postoperative neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

Complement activation contributes to perioperative neurocognitive disorders in mice

Xiong

Lü

Lin

et al. 2018

J Neuroinflammation

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BackgroundThe complement system plays an important role in many neurological disorders.Complement modulation, including C3/C3a receptor signaling, shows promising therapeutic effects on cognition and neurodegeneration. Yet, the implications for this pathway in perioperative neurocognitive disorders (PND) are not well established. Here, we evaluated the possible role for C3/C3a receptor signaling after orthopedic surgery using an established mouse model of PND.MethodsA stabilized tibial fracture surgery was performed in adult male C57BL/6 mice under general anesthesia and analgesia to induce PND-like behavior. Complement activation was assessed in the hippocampus and choroid plexus. Changes in hippocampal neuroinflammation, synapse numbers, choroidal blood-cerebrospinal fluid barrier (BCSFB) integrity, and hippocampal-dependent memory function were evaluated after surgery and treatment with a C3a receptor blocker.ResultsC3 levels and C3a receptor expression were specifically increased in hippocampal astrocytes and microglia after surgery. Surgery-induced neuroinflammation and synapse loss in the hippocampus were attenuated by C3a receptor blockade. Choroidal BCSFB dysfunction occurred 1 day after surgery and was attenuated by C3a receptor blockade. Administration of exogenous C3a exacerbated cognitive decline after surgery, whereas C3a receptor blockade improved hippocampal-dependent memory function.ConclusionsOrthopedic surgery activates complement signaling. C3a receptor blockade may be therapeutically beneficial to attenuate neuroinflammation and PND.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1292-4) contains supplementary material, which is available to authorized users.

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“…For example, while expression of C3aR and C5aR1 and 2 by human CD4 + T cells is broadly acknowledged, 15,72 their presence in mouse T cells is a matter of ongoing debate with some groups observing C3aR, or C5aR1 or 2 expression on resting or activated T cells 18,144 and others failing to replicate these findings. [145][146][147] Also, when detected, C5aR2 appears on the mouse T cell surface only upon activation, 148 in contrast to human T cells, where C5aR2 is constitutively found on the cell surface in both resting and activated cells. Also, there seem to be large conceptual divides with regard to the autocrine and intrinsic role of C3 in T cells.…”

Section: Current H Urdle S In D Iss Ec Ting the Complosome-me Tabolmentioning

confidence: 99%

Complement and human T cell metabolism: Location, location, location

West

Kunz

Kemper

2020

Immunological Reviews

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Immunological Reviews. 2020;295:68-81. wileyonlinelibrary.com/journal/imr 1 | INTRODUC TI ON Our contemporary immune system has evolved under the constant pressure from a broad range of pathogens that manipulate the host to enhance their own propagation. As diverse as the pathogenic threats are, ranging from intra-and extracellular bacteria, viruses, fungi, and complex parasites, as elegant and effective are the defense mechanisms developed and employed by the host to combat this constant onslaught. Particularly, the detection systems that are functioning as the first lines of defense against such invaders are formidable. If a microbe has managed to penetrate the protective physical barriers, such as the skin, or lung, a range of innate immune sensors either circulating in the blood, lymph, and interstitial fluids or expressed in and on scavenger and sentinel cells, such as neutrophils and microphages, detect the conserved pathogen-associated molecular patterns (PAMPs). These sensor systems comprise several pattern recognition receptors (PRRs) and include the Toll-like receptors (TLRs), the NOD-like receptors (NLRs), the retinoic acid-inducible gene-I (RIG)-like system, several distinct inflammasomes, and the complement system-derived receptors. 1,2 Activation of PRRs by a pathogen is most often triggered in several sensor systems in parallel and then initiates the general inflammatory reaction as well as tailored immune cell activation specifically effective toward the identified pathogen. The ability of PRR systems to decisively discriminate between a real threat, that is non-self and dangerous self via recognizing so-called danger-associated molecular patterns (DAMPs), and self and harmless alterations of self is critical for our health. Thus, there are several checks and balances build into the PRR systems that prevent unwanted reactions against sensed AbstractThe complement system represents one of the evolutionary oldest arms of our immune system and is commonly recognized as a liver-derived and serum-active system critical for providing protection against invading pathogens. Recent unexpected findings, however, have defined novel and rather "uncommon" locations and activities of complement. Specifically, the discovery of an intracellularly active complement system-the complosome-and its key role in the regulation of cell metabolic pathways that underly normal human T cell responses have taught us that there is still much to be discovered about this system. Here, we summarize the current knowledge about the emerging functions of the complosome in T cell metabolism. We further place complosome activities among the non-canonical roles of other intracellular innate danger sensing systems and argue that a "location-centric" view of complement evolution could logically justify its close connection with the regulation of basic cell physiology. K E Y W O R D S CD46, complement, complosome, metabolism, T cells | 69 WEST ET al.innocuous antigens. However, PRRs not only take care to contain tissue injury during their...

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Monitoring C3aR Expression Using a Floxed tdTomato-C3aR Reporter Knock-in Mouse

Cited by 60 publications

References 113 publications

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections

Complement activation contributes to perioperative neurocognitive disorders in mice

Complement and human T cell metabolism: Location, location, location

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