Complement is an integral part of the immune system and is activated by contact with foreign surface structures like lipopolysaccharide, mannose, necrotic cells, or by immune complexes. Upon complement activation, a proteolytic cascade is initiated and results in the release of components that contribute to host defense and inflammation. These include the anaphylatoxic peptides C3a and C5a, which mediate pro-inflammatory and immunemodulatory signals via their corresponding seven-transmembrane domain receptors, C3a receptor (C3aR) and C5a receptor (C5aR). The anaphylatoxin receptors are found on myeloid cells like granulocytes, mast cells, dendritic cells, monocytes and macrophages, and on non-myeloid cells such as neurons. In inflammation, they induce cytokine production, degranulation and chemotaxis of leukocytes, and vascular permeability.
Although the primary functions of the anaphylatoxins are in host defense, their excessive or sustained generation causes tissue damage and adversely affects the course of inflammatory conditions. C3a receptor (C3aR) is a well-established player in airway hyperresponsiveness, where it aggravates inflammation by promoting a T helper cell (Th)2-polarized response.Moreover, anaphylatoxin C3a receptor (C3aR) has been found harmful in P. aeruginosa pneumonia, whereas its functions in sepsis may vary depending on the tissue. C5a receptor (C5aR) has been shown to play deleterious roles in sepsis, airway hyperresponsiveness, rheumatoid arthritis, neurodegenerative diseases, and ischemia-reperfusion injury. Animal experiments and observations in patients provide evidence for complement activation in IBD, and for its participation in pathogenesis with mainly adverse effects. Mice deficient in the complement regulatory protein decay-accelerating factor, which protects host cells against assembly of C3 convertases early in the complement cascade, exhibit aggravated dextran sulfate sodium (DSS)-induced colitis. This indicates that downstream complement effectors are involved in bowel inflammation. To this effect, our group has previously investigated the role of C5a/C5aR in a mouse model of IBD, dextran sulfate sodium (DSS)-induced colitis, and found that targeted deletion of C5aR is protective in acute but disadvantageous in chronic colitis. Others have found C5aR antagonists or C5a antibodies to ameliorate trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats or mice .
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