Characterization of Anaphylatoxin Receptor Expression and C3a/C5a Functions in Anaphylatoxin Receptor Reporter Mice

Laumonnier, Yves; Karsten, Christian M.; Köhl, Gabriele; Köhl, Jörg

doi:10.1002/cpim.100

Cited by 8 publications

(5 citation statements)

References 46 publications

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“…Many studies including ours have reported the crucial role of CRP in accelerating apoptosis, 10,55 and crosstalk between apoptosis and autophagy has been confirmed that it can participate in the occurrence of DKD, 23,24 suggesting CRP is reasonable to participate in the pathogenesis of DKD. Moreover, considering that C3a is a multifunctional factor in inflammation, chemotaxis and cell activation, 43,44 we detected the direct effect of C3a on podocyte autophagy under high‐glucose conditions in vitro, and C3a‐induced podocyte autophagy under high‐glucose conditions was established in our study. C3a is inseparable from the presence of C3aR, and we further examined the regulation of CRP on C3aR expression and verified that CRP also participates in podocyte autophagy by inhibiting C3aR expression with its agonist and antagonist.…”

Section: Discussionmentioning

confidence: 52%

“…Anaphylatoxin C3a was originally considered to be a proinflammatory molecule produced in response to complement activation, and an increasing number of studies have shown that C3a is a potent effector in the chemotaxis and activation of a variety of target cells. 43,44 C3a augments the concentration of cytosolic free Ca 2+ in response to glucose, 45,46 and then the elevated cytosolic free Ca 2+ drives autophagy via the CaMKK/b-AMPK-TSC1/2-Rheb-mTORC1 signaling pathway. 47,48 Therefore, we examined the direct effect of C3a and C5a on podocyte autophagy under lowglucose (5 mM) and high-glucose (33 mM) conditions in a podocyte cell line MPC-5.…”

Section: C3a Promotes Podocyte Autophagy Under High-glucose Conditionsmentioning

confidence: 99%

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C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

Zhang

Gong

et al. 2022

The FASEB Journal

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Numerous studies have reported the pathogenic roles of C‐reactive protein (CRP) and complement activation in diabetic kidney disease (DKD) individually. However, considering the potent regulatory effect of CRP on complement activation, it remains unclear whether CRP participates in DKD pathogenesis by regulating complement activation. Moreover, this work focuses on complement activation in rats, which aims at settling the dispute that whether rat CRP can activate the complement system. To address this question, the complement effectors C3a, C5a, and C5b‐9 were examined in human patients with diabetic nephropathy (DN) and wt, Crp−/−, and huCRPtg rats with STZ‐diabetic DKD. The Crp−/− rats showed more C3a accumulation in blood and glomeruli than wt and huCRPtg rats. The balance between autophagy and apoptosis was evaluated in DKD rats, and Crp−/− rats showed increased podocyte autophagy compared with wt and huCRPtg rats. Meanwhile, stable CRP‐overexpression and CRP‐knockout cell lines were established and used to demonstrate that CRP suppresses C3a‐induced podocyte autophagy under high‐glucose conditions. We further verified that the inhibition of C3a‐induced podocyte autophagy by CRP was dependent on C3aR expression and that this effect could be reversed with a C3aR antagonist and agonist. Therefore, our findings provide evidence that CRP suppresses podocyte autophagy to accelerate the development of DKD by inhibiting C3a/C3aR axis signaling, which may help in the development of a new therapeutic strategy for the management of podocyte autophagy and DKD. In addition, rat CRP has been shown to be identical to human CRP in the activation of autologous complement and interspecific complement.

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Section: Discussionmentioning

confidence: 52%

Section: C3a Promotes Podocyte Autophagy Under High-glucose Conditionsmentioning

confidence: 99%

C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

Zhang

Gong

et al. 2022

The FASEB Journal

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“…The PCR-based identification of the floxed C5ar2-tdTomato gene in sorted immune cell populations was performed as previously described (50). Briefly, DNA from 1 × 10 5 sorted immune cells was extracted using the KAPA Express Extract Kit (Peqlab), according to manufacturer's protocol.…”

Section: Pcr-based Identification Of the Floxed C5ar2-tdtomato Gene I...mentioning

confidence: 99%

The complement receptor C5aR2 regulates neutrophil activation and function contributing to neutrophil-driven epidermolysis bullosa acquisita

et al. 2023

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IntroductionThe function of the second receptor for the complement cleavage product C5a, C5aR2, is poorly understood and often neglected in the immunological context. Using mice with a global deficiency of C5aR2, we have previously reported an important role of this receptor in the pathogenesis of the neutrophil-driven autoimmune disease epidermolysis bullosa acquisita (EBA). Based on in vitro analyses, we hypothesized that the absence of C5aR2 specifically on neutrophils is the cause of the observed differences. Here, we report the generation of a new mouse line with a LysM-specific deficiency of C5aR2.MethodsLysM-specific deletion of C5aR2 was achieved by crossing LysMcre mice with tdTomato-C5ar2fl/fl mice in which the tdTomato-C5ar2 gene is flanked by loxP sites. Passive EBA was induced by subcutaneous injection of rabbit anti-mouse collagen type VII IgG. The effects of targeted deletion of C5ar2 on C5a-induced effector functions of neutrophils were examined in in vitro assays.ResultsWe confirm the successful deletion of C5aR2 at both the genetic and protein levels in neutrophils. The mice appeared healthy and the expression of C5aR1 in bone marrow and blood neutrophils was not negatively affected by LysM-specific deletion of C5aR2. Using the antibody transfer mouse model of EBA, we found that the absence of C5aR2 in LysM-positive cells resulted in an overall amelioration of disease progression, similar to what we had previously found in mice with global deficiency of C5aR2. Neutrophils lacking C5aR2 showed decreased activation after C5a stimulation and increased expression of the inhibitory Fcγ receptor FcγRIIb.DiscussionOverall, with the data presented here, we confirm and extend our previous findings and show that C5aR2 in neutrophils regulates their activation and function in response to C5a by potentially affecting the expression of Fcγ receptors and CD11b. Thus, C5aR2 regulates the finely tuned interaction network between immune complexes, Fcγ receptors, CD11b, and C5aR1 that is important for neutrophil recruitment and sustained activation. This underscores the importance of C5aR2 in the pathogenesis of neutrophil-mediated autoimmune diseases.

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“…Recent generation of three new floxed reporter knock-in mouse lines for C3aR, C5aR1, and C5aR2, respectively ( 42 , 168 , 169 ), represents important progress in addressing these limitations. These mice allow both monitoring expression of these receptors in various tissues and temporally controlled tissue/cell-specific deletion of the receptors when crossed with an inducible Cre-expressing mouse line ( 170 ). Future studies using these new mouse lines as well as development of additional conditional-ready lines for other components of the complement system will be essential for dissecting the logic of cross-cellular interaction in executing many complement-mediated effects on the nervous system in health and disease.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain

Warwick

Keyes

Woodruff

et al. 2021

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Characterization of Anaphylatoxin Receptor Expression and C3a/C5a Functions in Anaphylatoxin Receptor Reporter Mice

Cited by 8 publications

References 46 publications

C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

C‐reactive protein inhibits C3a/C3aR‐dependent podocyte autophagy in favor of diabetic kidney disease

The complement receptor C5aR2 regulates neutrophil activation and function contributing to neutrophil-driven epidermolysis bullosa acquisita

The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain

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