Expression and Function of C5a Receptor in Mouse Microvascular Endothelial Cells

Laudes, Ines J.; Chu, Jeffrey C.; Huber‐Lang, Markus; Guo, Ruocheng; Riedemann, Niels C.; Sarma, J. Vidya; Mahdi, Fakhri; Murphy, Hedwig S.; Speyer, Cecilia L.; Lu, Kristina T.; Lambris, John D.; Zetoune, Firas S.; Ward, Peter A.

doi:10.4049/jimmunol.169.10.5962

Cited by 152 publications

(116 citation statements)

References 60 publications

(39 reference statements)

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“…Of the many effects that can occur through C5a receptor activation, induction of MCP-1 production, blocking apoptosis and promoting entry into the cell cycle are arguably the most important to our findings here. 26,[28][29][30][31] As the activating proteins in the complement systems of humans and mice are largely comparable, their study in mice can provide useful insights into human pathophysiology. 32 The complement regulators in mice are also largely conserved in humans with some notable differences.…”

Section: Discussionmentioning

confidence: 99%

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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The complex balance between the pro-activating and regulatory influences of the complement system can affect the pathogenesis of immune complex-mediated glomerulonephritis (ICGN). Key complement regulatory proteins include decay accelerating factor (DAF) and CD59, which inhibit C3 activation and C5b-9 generation, respectively. Both are glycosylphosphatidylinositol-linked cell membrane proteins, which are widely distributed in humans and mice. Chronic serum sickness induced by daily immunization with horse spleen apoferritin over 6 weeks was used to induce ICGN in DAF-, CD59-and DAF/CD59-deficient mice, with wild-type littermate mice serving as controls. Both DAF and DAF/CD59-deficient mice had an increased incidence of GN relative to wild-type controls associated with significantly increased glomerular C3 deposition. Disease expression in CD59-deficient mice was no different than wild-type controls. DAF-and DAF/CD59-deficient mice also had increased monocyte chemoattractant protein-1 mRNA expression and glomerular infiltration with CD45 þ leukocytes. Our findings suggest that activation of C3 is strongly associated with experimental ICGN while downstream formation of C5b-9 is of lesser pathogenic importance in this model.

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Section: Discussionmentioning

confidence: 99%

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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“…Because receptors for anaphylotoxin C5a (C5aR) are widely expressed in inflammatory cells and endothelial cells among others, 30,31 we hypothesized that C5a and C5aR interactions mediate cervical remodeling and PTD in LPS-and RU486-treated mice. To test this hypothesis we performed studies in C5aRϪ/Ϫ mice.…”

Section: C5a and C5ar Interaction Is A Critical Mediator Of Lps-and Rmentioning

confidence: 99%

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

González

Franzke

Yang

et al. 2011

The American Journal of Pathology

157

177

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Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication. Premature birth/delivery (PTD) is one of the most significant causes of perinatal mortality and morbidity in developed countries. Preterm infants suffer morbidities including respiratory distress, intraventricular hemorrhage, and cerebral palsy, among other serious diseases.1 These outcomes can have a life-long impact and more than $25 billion is spent each year to take care of these infants. Investigations to define the causes of PTD remain a challenge in the obstetrical field. Preterm labor is a multistage biochemical and biophysical process, during which changes in the myometrium and the cervix occur.The uterine cervix is a complex organ that undergoes extensive changes through gestation and parturition. These changes are a common first step in preterm parturition.2 As a gatekeeper for pregnancy, the cervix is a structural barrier that keeps the fetus inside the uterus until the end of gestation. Collagens, elastin, proteoglycans, and hyaluronate are responsible for the full tensile strength of the cervix.2 Ripening of the cervix is an important biological and clinical event required for a normal parturition. The process is gradual during pregnancy, with a fast final remodeling of the cervix before parturition. Increased collagen degradation and synthesis, and high activity of collagenases have been observed in the human cervix during final ripening.

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“…17 Recently, C5a has been shown to be involved in modulation of cytokine expression from various cell types. 18,19 C5a exerts its effects through the high-affinity receptors, mainly CD88 (C5aR). C5aR expression was not only described on myeloid cells, including neutrophils and macrophages, but also found on a variety of nonmyeloid cells in many organs, [20][21][22] which suggests the implication of C5a/C5aR signaling in the pathogenesis of organ-specific inflammation.…”

mentioning

confidence: 99%

Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis

Chen¹,

Yang

Gao

et al. 2011

Laboratory Investigation

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Complement represents a chief component of innate immunity in host defense. However, excessive complement activation has been involved in the pathogenesis of inflammatory diseases. In this study, we investigated the contribution of complement to intestinal pathology of patients and rodents with inflammatory bowel disease. The expression of complement effectors (C3a and C3) was increased remarkably in inflamed colons of IBD patients compared with those of normal counterparts. In accordance with this, the sustained activation of complement in serum and colon (including elevated C3a and C5a levels, enhanced hemolytic activity, downregulated expression of C5a receptors) was observed, following the establishment of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which peaked at 24 h. Mice pretreated with neutralizing anti-C5a antibodies (À2, 0, and 2 days after TNBS instillation) had significantly reduced weight loss and improved macroscopic/microscopic scores, comparable to the efficacy of prednisolone treatment. Strikingly, treatment with anti-C5a at 24 h after TNBS instillation showed remarkable therapeutic effects, whereas prednisolone did not. The efficacy of anti-C5a administration was associated with decreased release of proinflammatory chemokines and cytokines, inhibition of infiltration of neutrophils into colons, and enhanced Th2 response. These findings suggest a disease-promoting role of complement, particular C5a, in the pathology of TNBS-induced colitis in mice, indicating possible therapeutic potentials for C5a-specific antibody in IBD. The inflammatory bowel diseases (IBDs) encompassing Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of gastrointestinal tract, characterized by dysfunction of mucosal T cells, abnormal cytokine production, cellular inflammation, and ultimately damage to the intestinal lining. 1 Although the etiology of IBD remains unknown, there is circumstantial evidence to link IBD to the mucosal immune system's failure to attenuate immunity to endogenous antigen. 1 In recent years, several animal IBD models have been developed. 2,3 Although the relationship of many of these models to human disease is imperfect, the hapten-induced model of colonic inflammation in which 2,4,6-trinitrobenzene sulfonic acid (TNBS) is delivered intrarectally to BALB/c mice displays human CD-like features, notably predominantly IL-12-driving Th1 activity of the mucosal CD4 þ T-cell population and transmural mononuclear inflammation. 3 More recently, a pathogenic role of IL-23, the cytokine sharing p40 subunits with IL-12, has been evidenced in the development of CD. 4 Deficiency of IL-23-specific subunits (p19) leads to failure of colitis induction in a T-cell transfer model. This effect is attributed to suppression of IL-17 production and Th17 differentiation in the colons. 5 The factors that initiate intestinal pathology of CD and elicit Th1/Th17 immune reaction, however, are still

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Expression and Function of C5a Receptor in Mouse Microvascular Endothelial Cells

Cited by 152 publications

References 60 publications

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Complement Activation Triggers Metalloproteinases Release Inducing Cervical Remodeling and Preterm Birth in Mice

Blockade of complement activation product C5a activity using specific antibody attenuates intestinal damage in trinitrobenzene sulfonic acid induced model of colitis

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