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Sci Immunol. 2017 Jan;2(7). pii: eaaj2195. doi: 10.1126/sciimmunol.aaj2195. Epub 2017 Jan 20.

Complement C5a Receptor is the Key Initiator of Neutrophil Adhesion Igniting Immune Complex-induced Arthritis.

Author information

1
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
2
Vascular Research Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.

Abstract

The deposition of immune complexes (IC) in tissues induces a "type III hypersensitivity" that results in tissue damage and underlies the pathogenesis of many autoimmune diseases. The neutrophil is the first immune cell recruited into sites of IC deposition and plays a critical role in shaping the overall tissue response. However, the mechanism by which IC initiate and propagate neutrophil infiltration into tissue is not known. Here, using intravital multiphoton joint imaging of IC-induced arthritis in live mice, we found that the complement C5a receptor (C5aR) was the key initiator of neutrophil adhesion on joint endothelium. C5a presented on joint endothelium induced β2 integrin-dependent neutrophil arrest, facilitating neutrophil spreading and transition to crawling, and subsequent leukotriene B4 receptor (BLT1)-mediated extravasation of the first neutrophils. The chemokine receptor CCR1 promoted neutrophil crawling on the joint endothelium while CXCR2 amplified late neutrophil recruitment and survival once in the joint. Thus, imaging arthritis has defined a new paradigm for type III hypersensitivity where C5a directly initiates neutrophil adhesion on the joint endothelium igniting inflammation.

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