Monomeric C-reactive protein and inflammation in age-related macular degeneration

Chirco, Kathleen R.; Whitmore, S. Scott; Wang, Kai; Potempa, Lawrence A.; Halder, Jennifer A; Stone, Edwin M.; Tucker, Budd A.; Mullins, Robert F.

doi:10.1002/path.4766

Cited by 46 publications

(57 citation statements)

References 65 publications

(68 reference statements)

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“…However, the exact relationship between mCRP and MAC in AMD has not been assessed. While we did not see a correlation between mCRP and MAC abundance in RPE/choroid tissue, we have previously described co-localization between mCRP and MAC in the choriocapillaris 175 . In addition, complement activation studies revealed a trend toward more MAC on CECs pre-exposed to mCRP.…”

Section: Discussioncontrasting

confidence: 99%

“…We performed a total CRP ELISA to compare CRP levels based on 1) sample type and 2) CFH genotype. For the RPE/choroid tissue, we observed a non-significant trend toward increased CRP levels for high-risk eyes compared to low-risk eyes, which confirms ours and others' previous immunohistochemical findings 98,175 (Figure 16A). A significant difference based on CFH genotype was not observed in these donors when comparing serum CRP levels; however, there may be a trend toward more CRP in the high-risk donors (Figure 16B).…”

Section: Crp Accumulation In Amd Is Specific To the Choroidsupporting

confidence: 91%

“…We have recently shown that mCRP is present in the choriocapillaris of human donor eyes, with elevated mCRP levels observed in donors homozygous for the high-risk CFH genotype (Y402H) compared to controls 175 . Here, we aimed to 1) evaluate the source of mCRP in the choroid and 2) further assess the role of mCRP in inflammatory signaling and complement activation in the context of age-related macular degeneration.…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of pathophysiology and methods for regeneration of the choriocapillaris in age-related macular degeneration

Chirco¹

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lab. In addition to making time for our frequent chats, he has repeatedly gone out of his way to make sure I have everything I need to succeed as a grad student, including giving me the freedom to become an independent thinker and a more confident scientist. He has been, and will continue to be, a role model for me as I build my career. I would also like to acknowledge Dr. Budd Tucker for his mentorship, support, and positivity throughout my graduate school training, as well as all the members of my thesis committee, Dr. John Fingert, Dr. Val Sheffield, and Dr. Elliott Sohn, for their thoughtful advice and invaluable collaboration during my thesis work. I feel very fortunate to have been able to work alongside a group of such talented, supportive, and driven individuals that make up the WIVR. I would like to thank Dr. Ed Stone for leading this wonderful group and for his vital collaboration. To my fellow trainees, Dr. Kristan Worthington, Dr. Tas Sharma, and Joe Giacalone, thank you for your support, advice, and friendship, and for being the perfect scientific minds to bounce ideas off of. I will greatly miss working with you all. Thank you to my classmate and friend, Rachel Minerath, who has been the best listener, study buddy, and tennis partner over the last four years. I am so glad that I got to share all of the ups and downs of grad school with you. iv The Mullins Laboratory is made up of some amazing people whom I have had the privilege to work with on a daily basis. I would especially like to thank Miles Flamme-Wiese for helping me throughout my time in the lab, not only by making sure the lab runs smoothly, but also for teaching me various techniques early on. A special thank you goes to Jodi Graff and Dr. Mike Anderson who helped me stay positive and find my way in my first year of graduate school when my path was unclear. Your encouragement made all the difference during that time. I would especially like to thank my parents, Matt and Kathy, and my siblings, Kevin, Justin, Amy, and Scott, for their continuous support while I follow my dreams. To my fiancé, Mike, thank you for providing me with the best example of what hard work and dedication looks like. Your patience, love, and endless encouragement have meant the world to me. Thank you for always reminding me to not take myself so seriously and to have fun. It has truly been a blast growing and learning with you by my side.

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Section: Discussioncontrasting

confidence: 99%

Section: Crp Accumulation In Amd Is Specific To the Choroidsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Mechanisms of pathophysiology and methods for regeneration of the choriocapillaris in age-related macular degeneration

Chirco¹

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“…7 μm-thick cryosections were cut from each block and used for immunohistochemical and lectin histochemical analysis. Immunofluorescence was performed as described previously [22] utilizing the following primary antibodies: rabbit polyclonal anti-collagen IV (ab6586; Abcam, Cambridge, MA), mouse monoclonal anti-laminin (2E8; DSHB, Iowa City, IA), mouse monoclonal anti-elastin (MAB2503; EMD Millipore, Temecula, CA), rabbit polyclonal anti-CD31 (ab32457; Abcam), and rabbit polyclonal anti-VEGF (ab51745; Abcam). Biotinylated Ulex europaeus agglutinin-I (UEA-I; Vector Laboratories, Berlingame, CA) and biotinylated Sambucus nigra lectin (EBL; Vector Laboratories) were used for lectin histochemistry.…”

Section: Methodsmentioning

confidence: 99%

Preparation and evaluation of human choroid extracellular matrix scaffolds for the study of cell replacement strategies

et al. 2017

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Endothelial cells (ECs) of the choriocapillaris are one of the first cell types lost during age-related macular degeneration (AMD), and cell replacement therapy is currently a very promising option for patients with advanced AMD. We sought to develop a reliable method for the production of human choroidal extracellular matrix (ECM) scaffolds, which will allow for the study of choroidal EC (CEC) replacement strategies in an environment that closely resembles the native tissue. Human RPE/choroid tissue was treated sequentially with Triton X-100, SDS, and DNase to remove all native cells. While all cells were successfully removed from the tissue, collagen IV, elastin, and laminin remained, with preserved architecture of the acellular vascular tubes. The ECM scaffolds were then co-cultured with exogenous ECs to determine if the tissue can support cell growth and allow EC reintegration into the decellularized choroidal vasculature. Both monkey and human ECs took up residence in the choriocapillary tubes of the decellularized tissue. Together, these data suggest that our decellularization methods are sufficient to remove all cellular material yet gentle enough to preserve tissue structure and allow for the optimization of cell replacement strategies.

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“…Both FGF-2 and CRP have previously been demonstrated as potent promoters of cell motility of vascular cells including EC and smooth muscle cells [29,[52][53][54]. EC migration is an essential component of angiogenesis that requires a tight mechanically integrated molecular process, which is associated with the activation of intracellular pathways such as PI3K and phosphorylation of focal adhesion kinase (FAK) that converge on cytoskeleton remodelling.…”

Section: Discussionmentioning

confidence: 99%

Common Angiogenic Signaling Pathways Induced by Monomeric C - reactive protein and FGF-2 through MAPK and PI3K

Boras¹,

Slevin²,

Gilmore³

et al. 2018

Eur J Exp Bio

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Excessive angiogenesis (i.e. neovascularization) in atherosclerotic lesions, sites of dissociation of the inflammatory biomarker pentameric C-reactive protein (pCRP) into monomeric CRP (mCRP), represents a focus of plaque instability with haemorrhagic complications. We previously demonstrated mCRP pro-angiogenic effects on cultured aortic endothelial cells. However, mCRP effects in combination with FGF-2, pro-angiogenic factor released by activated macrophages infiltrating developing lesions, have not yet been described. Here, we examined in vitro the angiogenic capabilities of mCRP combined with FGF-2 by performing endothelial cell proliferation, migration, and differentiation including tube formation and spheroid sprouting assays. The signaling pathways were also investigated by Western blotting and all the cell-based assays were used with or without pharmacological inhibitors of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K) and γ-secretase, considered as key regulators of angiogenesis. We showed that mCRP-induced endothelial cell proliferation and migration required activation of PI3K pathway. MAPK pathway was essential in mCRP-induced endothelial cell proliferation and spheroid sprouting while γ-secretase activity was indispensable for mCRP-induced tube formation only. MAPK pathway was required in all FGF-2-stimulated angiogenic assays whereas γ-secretase slightly inhibited FGF-2 angiogenic effects. PI3K pathway was necessary for FGF-2 angiogenic activities except for cell differentiation. In most of the assays, the additive pro-angiogenic effects of mCRP combined to FGF-2 were mainly attenuated by PI3K and MAPK inhibitors. Altogether, mCRP and FGF-2 have common angiogenic signaling pathways through PI3K and MAPK. Thus, the therapeutic use of PI3K and MAPK inhibitors may inhibit this increased vascularization whilst reducing the haemorrhagic complications from unstable plaques.

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Monomeric C-reactive protein and inflammation in age-related macular degeneration

Cited by 46 publications

References 65 publications

Mechanisms of pathophysiology and methods for regeneration of the choriocapillaris in age-related macular degeneration

Mechanisms of pathophysiology and methods for regeneration of the choriocapillaris in age-related macular degeneration

Preparation and evaluation of human choroid extracellular matrix scaffolds for the study of cell replacement strategies

Common Angiogenic Signaling Pathways Induced by Monomeric C - reactive protein and FGF-2 through MAPK and PI3K

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