C5a desArg

Background

The complement component C5a is a small fragment of C5 cleaved by converting enzymes. C5a has a wide range of biological effects, including mediating inflammatory responses, acting as a sensitizing toxin, exerting chemotaxis, and immunomodulation. C5a desArg, the cleavage product of C5a, is a naturally glycosylated peptide consisting of 73 amino acids. This form of C5a is generated when the plasma enzyme carboxypeptidase removes the C-terminal arginine from C5a, rapidly metabolizing the original molecule. C5a desArg can bind to the C5a receptor (C5aR) and the C5a receptor-like 2 (C5L2) to exert its biological effects. C5a desArg retains only a fraction of the potency of C5a, exhibiting approximately 1% of its allergenic toxicity and chemical activity as well as 10% of its stimulatory activity. Despite these differences, C5a desArg is the predominant active form of C5a found in plasma and serum, making it a valuable indicator for measuring complement activation levels.

Fig.1 Generation and degradation of anaphylatoxins C3a and C5a.^{1, 4}

C5a in Sepsis

Sepsis is a complex and sometimes fatal illness caused by the body's overreaction to an infection. Studies have demonstrated that C5a is essential to the pathophysiology of sepsis. Elevated levels of C5a desArg have been consistently observed in the plasma or serum of septic patients and experimental models, suggesting its involvement in disease progression. During sepsis, excess C5a disrupts the normal function of neutrophils, a critical component of the immune system, and promotes apoptosis in various organs, including the thymus and adrenal gland. The C5a receptor (C5aR) is upregulated in multiple organs affected by sepsis. Additionally, C5L2 is also involved in C5a-mediated sepsis. It has been shown that C5aR and C5L2 signaling synergistically promote septic inflammation.

C5a in Neurodegenerative Diseases

Dysregulation of the complement system, particularly hyperactivation of the C5a component, has emerged as a critical factor in triggering inflammation in the central nervous system (CNS), especially in the context of aging, oxidative stress, and mitochondrial dysfunction. CC5a-mediated inflammation functions in various neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral malaria, and neuromyelitis optica spectrum disorder. These are primarily associated with the upregulation of C5a levels and downstream events triggered by C5a-C5aR1 signaling.

C5a in Cancer

Cancer cells exhibit an imbalance between immunosurveillance and immunosuppression, and C5a contributes to both. Specifically, C5a recruits myeloid-derived suppressor cells (MDSCs) and decreases the antitumor effects of CD8 T cells by mediating reactive oxygen and nitrogen production through C5aR on the membranes of MDSCs. Additionally, C5a can be produced through serine protease on cancer cells alone, without activating the complement system, which increases the level of C5a to promote cancer cell proliferation and metastasis. Moreover, C5a is involved in the induction of angiogenesis and the up-regulation of pro-inflammatory factors in the tumor microenvironment, both of which are essential cancer hallmarks. C5a has been proven effective in treating several cancers, including lung, breast, liver, kidney, colon, and ovarian cancers.

Fig.2 The function of complement in cancer metastasis.^{2, 4}

Creative Biolabs offers a C5a desArg protein and assay kit designed to facilitate functional assays and ELISA applications. If you want to know more about these products, please do not hesitate to contact us.

C5a Functional Service

Creative Biolabs supplies native human complement C5a desArg protein, meticulously designed to be crucial in exploring the interactions between C5a proteins and various molecular entities. These agents play a pivotal role in facilitating research aimed at formulating therapeutic approaches for a diverse range of diseases.

Fig.3 Binding interactions of C5a and C5a des Arg with human and rodent C5L2 and C5a receptors.^{3, 4}

C5L2 emerges as a previously unidentified receptor that interacts with the human complement factor C5a and its derivative, C5a des Arg. Employing an indirect immunofluorescence technique, researchers quantified the binding affinities of both C5a and C5a des Arg to wild type and mutant forms of C5L2 and C5aR. C5aR exhibits a preferential affinity for C5a and significantly reduced affinity for C5a des Arg, C5L2 shows comparable affinity for both molecules. The N terminus of C5aR features specific acidic and tyrosine residues vital for core C5a binding, while C5L2 distinctively recognizes C5a des Arg via unique residues in its N terminus. Studies in rodents reveal that C5L2 exhibits a higher affinity for C5a des Arg, underscoring its unique binding configuration, distinct from C5aR, and hinting at distinct receptor-ligand interaction mechanisms.

Creative Biolabs offers a comprehensive suite of services focused on C5a functionality, featuring assays specifically designed for C5a interactions and bespoke functional evaluations. These meticulously developed solutions are crafted to support esteemed clients in advancing their clinical and research projects.

References

1. McKenna, Sophie, et al. "The role of streptococcal cell-envelope proteases in bacterial evasion of the innate immune system." Journal of Innate Immunity 14.2 (2022): 69-88.
2. Kochanek, Dawn M., et al. "Complementing cancer metastasis." Frontiers in immunology 9 (2018): 1629.
3. Scola, Anne-Marie, et al. "The role of the N-terminal domain of the complement fragment receptor C5L2 in ligand binding." Journal of Biological Chemistry 282.6 (2007): 3664-3671.
4. Distributed under Open Access license CC BY 4.0, without modification.