Properdin Regulation of Complement Activation Affects Colitis in Interleukin 10 Gene–Deficient Mice

Jain, Umang; Midgen, Craig; Schwaeble, Wilhelm; Stover, Cordula M.; Stadnyk, Andrew W.

doi:10.1097/mib.0000000000000398

Cited by 16 publications

(13 citation statements)

References 51 publications

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“…In vivo mouse models have provided evidence for other potential consequences of systemic, long‐term properdin inhibition. P −/− mice exhibited worsened colitis, associated with decreased infiltration of neutrophils into the intestine and corresponding increases in bacterial burden in an IL‐10 −/− model of inflammatory bowel disease . Properdin deficiency was also shown to be detrimental in a mouse model of infectious colitis utilizing Citrobacter rodentium .…”

Section: Potential For Properdin Inhibitors As Long‐term Prophylacticmentioning

confidence: 99%

“…P −/− mice exhibited worsened colitis, associated with decreased infiltration of neutrophils into the intestine and corresponding increases in bacterial burden in an IL-10 −/− model of inflammatory bowel disease. 184 Properdin deficiency was also shown to be detrimental in a mouse model of infectious colitis utilizing Citrobacter rodentium. Increased pathogenesis in this model was related to an increase in infiltrating neutrophils and macrophages as a result of a decreased ability of intestinal epithelial cells to control initial bacterial burden, which was shown to be dependent on properdin-mediated generation of C5a.…”

Section: Potential Consequences Of Properdin Inhibitionmentioning

confidence: 99%

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Properdin: a tightly regulated critical inflammatory modulator

Blatt

Pathan

Ferreira

2016

Immunological Reviews

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SummaryThe complement alternative pathway is a powerful arm of the innate immune system that enhances diverse inflammatory responses in the human host. Key to the effects of the alternative pathway is properdin, a serum glycoprotein that can both initiate and positively regulate alternative pathway activity. Properdin is produced by many different leukocyte subsets and circulates as cyclic oligomers of monomeric subunits. While the formation of non‐physiological aggregates in purified properdin preparations and the presence of potential properdin inhibitors in serum have complicated studies of its function, properdin has, regardless, emerged as a key player in various inflammatory disease models. Here, we review basic properdin biology, emphasizing the major hurdles that have complicated the interpretation of results from properdin‐centered studies. In addition, we elaborate on an emerging role for properdin in thromboinflammation and discuss the potential utility of properdin inhibitors as long‐term therapeutic options to treat diseases marked by increased formation of platelet/granulocyte aggregates. Finally, we describe the interplay between properdin and the alternative pathway negative regulator, Factor H, and how aiming to understand these interactions can provide scientists with the most effective ways to manipulate alternative pathway activation in complex systems.

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Section: Potential For Properdin Inhibitors As Long‐term Prophylacticmentioning

confidence: 99%

Section: Potential Consequences Of Properdin Inhibitionmentioning

confidence: 99%

Properdin: a tightly regulated critical inflammatory modulator

Blatt

Pathan

Ferreira

2016

Immunological Reviews

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“…On the contrary, in cases of infection where complement is directed to the invading pathogen, absence of properdin was often found detrimental for the host. Properdin deficiency has been associated with an exacerbated disease outcome in models of polymicrobial septic peritonitis [ 7 ], colitis [ 50 , 51 ], small intestinal mucositis [ 106 ], LPS-induced non-septic shock [ 107 ], and Listeria -induced septicemia [ 108 ]. In these cases, properdin-deficient mice likely had a detrimental outcome due to compromised host defense against the microbial intruder, indicating properdin played a crucial role in this process.…”

Section: Clinical Significance Of Properdinmentioning

confidence: 99%

The role of properdin in complement-mediated renal diseases: a new player in complement-inhibiting therapy?

et al. 2018

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Properdin is known as the only positive regulator of the complement system. Properdin promotes the activity of this defense system by stabilizing its key enzymatic complexes: the complement alternative pathway (AP) convertases. Besides, some studies have indicated a role for properdin as an initiator of complement activity. Though the AP is a powerful activation route of the complement system, it is also involved in a wide variety of autoimmune and inflammatory diseases, many of which affect the kidneys. The role of properdin in regulating complement in health and disease has not received as much appraisal as the many negative AP regulators, such as factor H. Historically, properdin deficiency has been strongly associated with an increased risk for meningococcal disease. Yet only recently had studies begun to link properdin to other complement-related diseases, including renal diseases. In the light of the upcoming complement-inhibiting therapies, it is interesting whether properdin can be a therapeutic target to attenuate AP-mediated injury. A full understanding of the basic concepts of properdin biology is therefore needed. Here, we first provide an overview of the function of properdin in health and disease. Then, we explore its potential as a therapeutic target for the AP-associated renal diseases C3 glomerulopathy, atypical hemolytic uremic syndrome, and proteinuria-induced tubulointerstitial injury. Considering current knowledge, properdin-inhibiting therapy seems promising in certain cases. However, knowing the complexity of properdin's role in renal pathologies in vivo, further research is required to clarify the exact potential of properdin-targeted therapy in complement-mediated renal diseases.

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“…In the small intestines, exposed to high fat diet, the complement transcriptome is increased [103] as epithelial cells react to support the mucosal barrier [104]. In a condition where epithelial integrity is compromised, we found that the absence of properdin led to enhanced bacterial translocation [105]. Therefore, we suggest that altered intestinal permeability in KO (which we did not measure) yields higher levels of endotoxin, fatty acids and lipids (which we measured).…”

Section: Discussionmentioning

confidence: 68%

Complement Properdin Regulates the Metabolo-Inflammatory Response to a High Fat Diet

et al. 2020

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Background and objectives: Overnutrition leads to a metabolic and inflammatory response that includes the activation of Complement. Properdin is the only amplifier of complement activation and increases the provision of complement activation products. Its absence has previously been shown to lead to increased obesity in mice on a high fat diet. The aim of this study was to determine ways in which properdin contributes to a less pronounced obese phenotype. Materials and Methods: Wild type (WT) and properdin deficient mice (KO) were fed a high-fat diet (HFD) for up to 12 weeks. Results: There was a significant increase in liver triglyceride content in the KO HFD group compared to WT on HFD. WT developed steatosis. KO had an additional inflammatory component (steatohepatitis). Analysis of AKT signalling by phosphorylation array supported a decrease in insulin sensitivity which was greater for KO than WT in liver and kidney. There was a significant decrease of C5L2 in the fat membranes of the KO HFD group compared to the WT HFD group. Circulating microparticles in KO HFD group showed lower presence of C5L2. Expression of the fatty acid transporter CD36 in adipose tissue was increased in KO on HFD and was also significantly increased in plasma of KO HFD mice compared to WT on HFD. CD36 was elevated on microparticles from KO on HFD. Ultrastructural changes consistent with obesity-associated glomerulopathy were observed for both HFD fed genotypes, but tubular strain was greater in KO. Conclusion: Our work demonstrates that complement properdin is a dominant factor in limiting the severity of obesity-associated conditions that impact on liver and kidney. The two receptors, C5L2 and CD36, are downstream of the activity exerted by properdin.

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Properdin Regulation of Complement Activation Affects Colitis in Interleukin 10 Gene–Deficient Mice

Abstract: Complement is activated in the IL-10(-/-) mouse mucosa in a properdin-dependent manner. In the absence of terminal complement activation, the inflammation is heightened, likely due to a lack of neutrophil control over microbes escaping from the intestines.

Cited by 16 publications

References 51 publications

Properdin: a tightly regulated critical inflammatory modulator

Properdin: a tightly regulated critical inflammatory modulator

The role of properdin in complement-mediated renal diseases: a new player in complement-inhibiting therapy?

Complement Properdin Regulates the Metabolo-Inflammatory Response to a High Fat Diet

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