Cutting Edge: Targeted Disruption of the C3a Receptor Gene Demonstrates a Novel Protective Anti-Inflammatory Role for C3a in Endotoxin-Shock

Kildsgaard, Jens; Hollmann, Travis J.; Matthews, K.W.; Bian, Ka; Murad, Ferid; Wetsel, Rick A.

doi:10.4049/jimmunol.165.10.5406

Cited by 175 publications

(149 citation statements)

References 17 publications

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“…At the same time, complement proteins such as C3a have shown antiinflammatory properties that might preclude the further amplification of complement activation products necessary for complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. In a murine model of sepsis, C3aR−/− mice showed greater mortality in response to lipopolysaccharide shock when compared with wild-type mice, with concomitant increases in the proinflammatory cytokine IL-1β (150). Furthermore, C3a/GFAP mice, which express biologically active C3a exclusively in the central nervous system, were more resistant to lipopolysaccharide shock than their wild-type and C3aR−/− counterparts (151).…”

Section: Complement and Immunosurveillancementioning

confidence: 91%

Cancer and the Complement Cascade

Rutkowski

Sughrue

Kane

et al. 2010

Molecular Cancer Research

225

256

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Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia.

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Section: Complement and Immunosurveillancementioning

confidence: 91%

Cancer and the Complement Cascade

Rutkowski

Sughrue

Kane

et al. 2010

Molecular Cancer Research

225

256

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“…The results convincingly demonstrate that a number of compounds (7, 8, 13, 16 and 17) have equipotent agonist activity to the protein C3a, as measured by induction of intracellular Ca 2 þ release in human macrophages ( Table 1). The most potent compound (17) was examined in more detail in other cellular assays, with mimicry of potent C3a function also extending to C3aR-mediated expression of all seven selected inflammatory genes in human macrophages and to C3aR-mediated degranulation of human mast cells. These immunostimulating properties for 17 are the same as for human C3a, validating successful functional mimicry of a protein by a small molecule across a range of inflammatory and cellular readouts.…”

Section: Resultsmentioning

confidence: 99%

“…C3a is a powerful proinflammatory agent that recruits immune cells to sites of infection (chemotaxis) and induces immune cells to secrete bactericidal agents (via degranulation) as well as inflammatory cytokines 13,14 . Overexpression of C3a/C3aR or sustained activation of its receptor can lead to inflammatory diseases, including allergies 10 , asthma 15 , arthritis 16 , sepsis 17 , lupus 18 , diabetes 19 , psoriasis 20 , nephropathy 21 , ischaemia-reperfusion injury 22 , obesity, and metabolic and cardiovascular dysfunction 23 . C3a also reportedly has antimicrobial 24 and antifungal 25 activities.…”

mentioning

confidence: 99%

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

et al. 2013

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A significant challenge in chemistry is to rationally reproduce the functional potency of a protein in a small molecule, which is cheaper to manufacture, non-immunogenic, and also both stable and bioavailable. Synthetic peptides corresponding to small bioactive protein surfaces do not form stable structures in water and do not exhibit the functional potencies of proteins. Here we describe a novel approach to growing small molecules with protein-like potencies from a functionally important amino acid of a protein. A 77-residue human inflammatory protein (complement C3a) important in innate immunity is rationally transformed to equipotent small molecules, using peptide surrogates that incorporate a turninducing heterocycle with correctly positioned hydrogen-bond-accepting atoms. Small molecule agonists (molecular weight o500 Da) examined for receptor affinity and cellular responses have the same high potencies, functional profile and specificity of action as C3a protein, but greater plasma stability and bioavailability.

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“…C3aR knockout mice were generated as described (57). For the LPS studies, C57BL/6J mice were injected i.p.…”

Section: Micementioning

confidence: 99%

Expression of the Complement Anaphylatoxin C3a and C5a Receptors on Bronchial Epithelial and Smooth Muscle Cells in Models of Sepsis and Asthma

Drouin¹,

Kildsgaard²,

Haviland³

et al. 2001

The Journal of Immunology

Self Cite

193

149

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The presence of the complement-derived anaphylatoxin peptides, C3a and C5a, in the lung can induce respiratory distress characterized by contraction of the smooth muscle walls in bronchioles and pulmonary arteries and aggregation of platelets and leukocytes in pulmonary vessels. C3a and C5a mediate these effects by binding to their specific receptors, C3aR and C5aR, respectively. The cells that express these receptors in the lung have not been thoroughly investigated, nor has their expression been examined during inflammation. Accordingly, C3aR and C5aR expression in normal human and murine lung was determined in this study by immunohistochemistry and in situ hybridization. In addition, the expression of these receptors was delineated in mice subjected to LPS- and OVA-induced models of inflammation. Under noninflamed conditions, C3aR and C5aR protein and mRNA were expressed by bronchial epithelial and smooth muscle cells of both human and mouse lung. C3aR expression increased significantly on both bronchial epithelial and smooth muscle cells in mice treated with LPS; however, in the OVA-challenged animals only the bronchial smooth muscle cells showed increased C3aR expression. C5aR expression also increased significantly on bronchial epithelial cells in mice treated with LPS, but was not elevated in either cell type in the OVA-challenged mice. These results demonstrate the expression of C3aR and C5aR by cells endogenous to the lung, and, given the participation of bronchial epithelial and smooth muscle cells in the pathology of diseases such as sepsis and asthma, the data suggest a role for these receptors during lung inflammation.

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Cutting Edge: Targeted Disruption of the C3a Receptor Gene Demonstrates a Novel Protective Anti-Inflammatory Role for C3a in Endotoxin-Shock

Cited by 175 publications

References 17 publications

Cancer and the Complement Cascade

Cancer and the Complement Cascade

Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

Expression of the Complement Anaphylatoxin C3a and C5a Receptors on Bronchial Epithelial and Smooth Muscle Cells in Models of Sepsis and Asthma

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