Abstract
IntroductionProperdin amplifies the alternative pathway of complement activation. In the present study, we evaluated its role in the development of collagen antibody-induced arthritis (CAIA).MethodsArthritis was induced by intraperitoneal injection of a collagen antibody cocktail into properdin-deficient (KO) and wild-type (WT) C57BL/6 mice. Symptoms of disease were evaluated daily. The degree of joint damage was assessed histologically and with immunostaining for bone-resorption markers. Phenotypes of cell populations, their receptor expression, and intracellular cytokine production were determined with flow cytometry. Osteoclast differentiation of bone marrow (BM) precursors was evaluated by staining for tartrate-resistant acid phosphatase (TRAP).ResultsProperdin-deficient mice developed less severe CAIA than did WT mice. They showed significantly improved clinical scores and downregulated expression of bone-resorption markers in the joints at day 10 of disease. The frequencies of Ly6G+CD11b+ cells were fewer in BM, blood, and synovial fluid (SF) of KO than of WT CAIA mice. The receptor activator of nuclear factor κB ligand (RANKL) was downregulated on arthritic KO neutrophils from BM and the periphery. Decreased C5a amounts in KO SF contributed to lower frequencies of CD5aR+-bearing neutrophils. In blood, surface C5aR was detected on KO Ly6G+ cells as a result of low receptor engagement. Circulating CD4+ T cells had an altered ability to produce interleukin (IL)-17 and interferon (IFN)-γ and to express RANKL. In KO CAIA mice, decreased frequencies of CD4+ T cells in the spleen were related to low CD86 expression on Ly6GhighCD11b+ cells. Arthritic KO T cells spontaneously secreted IFN-γ but not IL-17 and IL-6, and responded to restimulation with less-vigorous cytokine production in comparison to WT cells. Fewer TRAP-positive mature osteoclasts were found in KO BM cell cultures.ConclusionsOur data show that the active involvement of properdin in arthritis is related to an increased proinflammatory cytokine production and RANKL expression on immune cells and to a stimulation of the RANKL-dependent osteoclast differentiation.
Highlights
Properdin amplifies the alternative pathway of complement activation
Histologic examination showed a massive presence of inflammatory cells in the synovial tissue and cartilage of WT mice, which was markedly reduced in KO mice
Additional file 1: Fcg receptors (FcgRs) expression on synovial and blood neutrophils and on monocytes in properdin-deficient mice with collagen antibody-induced arthritis (CAIA). (A) FcgR was expressed on blood wild-type Ly6G+ cells but not on properdindeficient cells, as shown in one individual experiment
Summary
We evaluated its role in the development of collagen antibody-induced arthritis (CAIA). The factor is expressed in peripheral blood T cells [8] and monocytes [9] and is released from neutrophil granules after stimulation [10]. The latter process is controlled by a particular C3 fragment in a way that intravascular AP activation is limited, but AP is augmented at sites of inflammation [11]. The amelioration of disease activity has been observed in factor B- or C3deficient mice with CAIA but not in mice lacking C4, C1q, mannose-binding lectin (MBL) A, C, or both C1q and MBL [14]. The injection of collagen antibodies into C5-deficient mice does not promote disease pathology [15]
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