C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma

Nabizadeh, Jamileh A.; Manthey, Helga D.; Panagides, Nadya; Steyn, Frederik J.; Lee, John D.; Li, Xaria X.; Akhir, Fazrena Nadia Md; Chen, Wei-Yu; Boyle, Glen M.; Taylor, Stephen M.; Woodruff, Trent M.; Rolfe, Barbara E.

doi:10.1096/fj.201800980rr

Cited by 23 publications

(14 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, C5aR2 instead displays a pro-inflammatory role in several autoimmune diseases, resulting in an enigmatic and controversial role 41 . In consistent with a previous report in a melanoma bearing murine model 42 , we showed that in contrast to C5aR1, C5aR2 deficiency accelerated tumor development, suggesting an anti-inflammatory role of C5aR2 in AOM/DSS-induced CRC tumorigenesis. The result may also explain the observation that tumor burden in C5- deficient mice is greater than in C5ar1- deficient mice.…”

Section: Discussionsupporting

confidence: 93%

C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Ding¹,

Li²,

Li³

et al. 2020

Theranostics

View full text Add to dashboard Cite

Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis. Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/ dextran sulfate sodium (DSS) in Wild-type (WT), C3 -, C5 -, C5ar1 -, and C5ar2 -deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis. Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1 , but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8 + T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis. Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy.

show abstract

Section: Discussionsupporting

confidence: 93%

C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Ding¹,

Li²,

Li³

et al. 2020

Theranostics

View full text Add to dashboard Cite

show abstract

“…C5a can interact with two different receptors, C5aR1 and C5aR2, with opposite functions. C5aR1 seems to have pro-tumoral role, whereas C5aR2 has more limited impact but tends to modulate the tumor growth [14].…”

Section: Therapeutic Inhibition Of C5ar1 On Tumor Cells Versus On Immmentioning

confidence: 95%

“…Anaphylatoxins (C3a and C5a) are released in the circulation and have an important role to induce inflammation and activate cells expressing anaphylatoxin receptors (C3aR, C5aR1/C5aR2). C5aR1 and C5aR2 seem to have opposite effects, especially in the tumor context [14]. MAC formed by the association of C5b molecule with C6 that acquire the ability to interact with lipid bilayer, the C7 and C8 molecules bind C5b and insert into lipid bilayer, then several molecules of C9 polymerize creating the lytic pore, causing membrane permeabilization, cell activation and/or the cell death [15].…”

Section: Complement Effector Pathwaysmentioning

confidence: 99%

Complement System: Promoter or Suppressor of Cancer Progression?

et al. 2020

View full text Add to dashboard Cite

Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.

show abstract

“…Over the last few years, evidence has indicated that C5a activation triggers a cascade of events that are involved in the pathophysiology of PN and in the genesis of painful states of neuro-inflammation [8]. C5a exerts its biological functions by binding two receptors, C5a receptor-like 1 (C5aR1, also referred to as CD88), a class A seven-transmembrane Gprotein-coupled receptor (GPCR), and C5a receptor-like 2 (C5aR2, also known as C5L2 or GPR77) [33], a homolog of C5aR1, but which is not coupled to intracellular heterotrimeric G-proteins due to a mutation in G-protein recognition sequence. C5aR1 is expressed by a broad range of cell types, including all cells of myeloid origin (neutrophils, eosinophils, monocytes, macrophages, dendritic cells, mast cells), lymphocytes, and non-myeloid cells, such as lung, liver, kidney, skin, and central nervous system (CNS) cells [5,34].…”

Section: Peripheral Neuropathies and C5a/c5ar1 Axismentioning

confidence: 99%

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

et al. 2021

View full text Add to dashboard Cite

The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.

show abstract

C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma

Cited by 23 publications

References 63 publications

C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation

Complement System: Promoter or Suppressor of Cancer Progression?

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

Contact Info

Product

Resources

About