The anaphylatoxin C5a: Structure, function, signaling, physiology, disease, and therapeutics

Ghosh, Manaswini; Rana, Soumendra

doi:10.1016/j.intimp.2023.110081

Cited by 24 publications

(16 citation statements)

References 355 publications

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“…Three anti-human C5aR monoclonal antibodies, S5/1, P12/1, and 8D6, were evaluated on leukocytes from human blood by both flow cytometry and immunohistochemistry (IHC). All clones readily detected C5aR on neutrophils as expected (3, 26), when compared to isotype controls (Supplemental Figure 1). Despite similar staining of leukocytes, the clones had divergent expression patterns by IHC in sections from formalin-fixed, paraffin-embedded (FFPE) samples of non-diseased human kidney (Figure 1A-D).…”

Section: Resultssupporting

confidence: 63%

“…The peptide C5a is produced from the cleavage of complement factor C5 and is a ligand for the G-protein coupled receptor C5aR (C5aR1 or CD88) and the atypical GPCR C5L2 (C5aR2 or CD77) (2). C5aR is expressed in circulating myeloid cells and contributes to inflammatory responses via activation of these cell types (3). Genetic deletion and pharmacological inhibition studies in disease models have implicated C5aR in the pathogenesis of multiple diseases including ANCA-associated vasculitis, kidney fibrosis, infection, and cancer (4–7).…”

Section: Introductionmentioning

confidence: 99%

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C5aR Expression in Kidney Tubules, Macrophages and Fibrosis

Dunlap,

Zhao,

Ertl

et al. 2023

Preprint

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The anaphylatoxin C5a and its receptor C5aR (CD88) are complement pathway effectors implicated in renal diseases, including ANCA-associated vasculitis. We investigated the kidney expression of C5aR and a second C5a receptor C5L2 by using immunohistochemistry and in situ hybridization on formalin-fixed, paraffin-embedded human and mouse kidney. C5aR was detected on interstitial macrophages and in multiple tubular regions, both distal and proximal; C5L2 had a similar expression pattern. The 5/6 nephrectomy model of chronic kidney injury exhibited increased C5aR expression by infiltrating cells within the fibrotic regions. Functional assessment of myeloid C5aR in vitro revealed that C5a induced the expression of chemokines and remodeling factors by macrophages, including CCL-3/-4/-7,-20, MMP-1/-3/-8/-12, and F3, and promoted survival by blocking neutrophil apoptosis. C5a activity was C5aR dependent, as demonstrated by reversal with the C5aR inhibitor avacopan. Collectively, these results suggest that myeloid C5aR may induce excessive inflammation in the kidney via immune cell recruitment, extracellular matrix destruction, and remodeling, resulting in fibrotic tissue deposition.

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Section: Resultssupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

C5aR Expression in Kidney Tubules, Macrophages and Fibrosis

Dunlap,

Zhao,

Ertl

et al. 2023

Preprint

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“…Therefore, a multipronged therapeutic approach targeting either the SARS-CoV-2 or the host cell proteins and pathways has been largely explored and evaluated across the globe to restrict the spread and manage the severity of immunoinflammation triggered by COVID19. To calm the “cytokine storm” associated with COVID19, inhibitors targeting the chemokines, cytokines, antibodies targeting complement proteins like C5a, , and corticosteroids have been predominantly used in the clinic. In addition, repurposing of small-molecule drugs, − including antibody-like peptides targeting C5a, have also been described in the literature to potentially calm the severe inflammatory response of the immune system.…”

Section: Discussionmentioning

confidence: 99%

A Rationally Designed Synthetic Antiviral Peptide Binder Targeting the Receptor-Binding Domain of SARS-CoV-2

Behera,

Gupta,

Ghosh

et al. 2024

J. Phys. Chem. B

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus, is the causative agent responsible for the spread of the COVID19 pandemic across the globe. The global impact of the COVID19 pandemic, the successful approval of vaccines for controlling the pandemic, and the further resurgence of COVID19 necessitate the exploration and validation of alternative therapeutic avenues targeting SARS-CoV-2. The initial entry and further invasion by SARS-CoV-2 require strong protein−protein interactions (PPIs) between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptors expressed on the cell surfaces of various tissues. In principle, disruption of the PPIs between the RBD of SARS-CoV-2 and the ACE2 receptor by designer peptides with optimized pharmacology appears to be an ideal choice for potentially preventing viral entry with minimal immunogenicity. In this context, the current study describes a short, synthetic designer peptide (codenamed SR16, ≤18 aa, molecular weight ≤2.5 kDa), which has a few noncoded amino acids, demonstrates a helical conformation in solution, and also engages the RBD of SARS-CoV-2 through a high-affinity interaction, as judged from a battery of biophysical studies. Further, the designer peptide demonstrates resistance to trypsin degradation, appears to be nontoxic to mammalian cells, and also does not induce hemolysis in freshly isolated human erythrocytes. In summary, SR16 appears to be an ideal peptide binder targeting the RBD of SARS-CoV-2, which has the potential for further optimization and development as an antiviral agent targeting SARS-CoV-2.

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“…The complement system, 1 a cocktail of plasma proteins, is a vital armory in the first line of defense of the immune system, whose regulated activation through the proteolytic cascade rapidly kills and eliminates the invading microbes nonspecifically, protecting the body from microbial invasion under normal circumstances. However, dysregulation of complement 2 is associated with the risk of severe microbial infections like sepsis 3 . On the other hand, as a part of the natural self‐survival process, microbes like bacteria (nonpathogenic and pathogenic) have enabled themselves with a formidable defense system for protection from the world of chemicals around them, which is the primary evolutionary tenet behind microbial resistance 4 .…”

Section: Introductionmentioning

confidence: 99%

“…protecting the body from microbial invasion under normal circumstances. However, dysregulation of complement 2 is associated with the risk of severe microbial infections like sepsis. 3 On the other hand, as a part of the natural self-survival process, microbes like bacteria (nonpathogenic and pathogenic) have enabled themselves with a formidable defense system for protection from the world of chemicals around them, which is the primary evolutionary tenet behind microbial resistance.…”

mentioning

confidence: 99%

A rationally engineered small antimicrobial peptide with potent antibacterial activity

Behera,

Ghosh,

Gupta

et al. 2023

J of Cellular Biochemistry

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Antimicrobial resistance (AMR) is a silent pandemic declared by the WHO that requires urgent attention in the post‐COVID world. AMR is a critical public health concern worldwide, potentially affecting people at different stages of life, including the veterinary and agriculture industries. Notably, very few new‐age antimicrobial agents are in the current developmental pipeline. Thus, the design, discovery, and development of new antimicrobial agents are required to address the menace of AMR. Antimicrobial peptides (AMPs) are an important class of antimicrobial agents for combating AMR due to their broad‐spectrum activity and ability to evade AMR through a multimodal mechanism of action. However, molecular size, aggregability, proteolytic degradation, cytotoxicity, and hemolysis activity significantly limit the clinical application of natural AMPs. The de novo design and engineering of a short synthetic amphipathic AMP (≤16 aa, Mol. Wt. ≤ 2 kDa) with an unusual architecture comprised of coded and noncoded amino acids (NCAAs) is presented here, which demonstrates potent antibacterial activity against a few selected bacterial strains mentioned in the WHO priority list. The designer AMP is conformationally ordered in solution and effectively permeabilizes the outer and inner membranes, leading to bacterial growth inhibition and death. Additionally, the peptide is resistant to proteolysis and has negligible cytotoxicity and hemolysis activity up to 150 μM toward cultured human cell lines and erythrocytes. The designer AMP is unique and appears to be a potent therapeutic candidate, which can be subsequently subjected to preclinical studies to explicitly understand and address the menace of AMR.

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The anaphylatoxin C5a: Structure, function, signaling, physiology, disease, and therapeutics

Cited by 24 publications

References 355 publications

C5aR Expression in Kidney Tubules, Macrophages and Fibrosis

C5aR Expression in Kidney Tubules, Macrophages and Fibrosis

A Rationally Designed Synthetic Antiviral Peptide Binder Targeting the Receptor-Binding Domain of SARS-CoV-2

A rationally engineered small antimicrobial peptide with potent antibacterial activity

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