Neutrophils in a mouse model of autoantibody‐mediated arthritis: Critical producers of Fc receptor γ, the receptor for C5a, and lymphocyte function−associated antigen 1

Abstract

Objective. Neutrophils represent a prominent component of inflammatory joint effusions and are required for synovial inflammation in mouse models, but the mechanisms are poorly understood. In this study, we developed a system with which to test the importance of the production of specific factors by neutrophils in a mouse model of arthritis.Methods. Neutrophil-deficient Gfi-1 -/-mice were administered sublethal doses of radiation and were then engrafted with donor bone marrow cells (BMCs), which resulted in the production of mature neutrophils within 2 weeks. By reconstituting with BMCs from mice lacking selected proinflammatory factors, we generated mice that specifically lacked these factors on their neutrophils. Arthritis was initiated by transfer of K/BxN serum to identify the role of defined neutrophil factors on the incidence and severity of arthritis. The inability of neutrophils to make tumor necrosis factor or to express receptors for tumor necrosis factor or IL-1 had no effect on arthritis. Results. Neutrophils lacking the signaling chain of stimulatory Fc receptors (FcR␥Conclusion. A novel transfer system was developed to identify neutrophil production of FcR␥, C5aR, and CD11a/LFA-1 as critical components of autoantibody-mediated arthritis. Neutrophil production of IL-1 and leukotriene B 4 likely contributes to inflammation but is not essential. Molecular requirements for neutrophil influx into joints become more permissive after inflammation is initiated.A variety of autoimmune responses in mice can lead to inflammatory arthritis, with histologic features resembling those of RA: expansion of type A and type B synoviocytes, angiogenesis, recruitment of lymphocytes to the synovium and neutrophils to the joint fluid, and destruction of cartilage and bone. Many of these arthritis models are dependent on breaking T cell tolerance, followed by the production of autoantibodies (1). The

Regulation of systemic and local myeloid cell subpopulations by bone marrow cell–derived granulocyte–macrophage colony‐stimulating factor in experimental inflammatory arthritis

“…This finding of a normal early, predominantly neutrophil, response but a later defective macrophage response in K/BxN serum-transfer arthritis induced in GM-CSF Ϫ/Ϫ mice is similar to what we observed in the methylated bovine serum albumin-induced peritonitis model in these mice (22). It has been suggested that macrophages are most likely important after the initiation of K/BxN serum-transfer arthritis, being a major source of proinflammatory cytokines (45), whereas neutrophils are required in the early stage involving the vascular permeability that precedes disease onset (46).…”

Cutting Edge: The Murine High-Affinity IgG Receptor FcγRIV Is Sufficient for Autoantibody-Induced Arthritis

“…1C), as reported for wt mice (9,10). A recent report demonstrating that K/BxN-PA could be restored in neutrophil-deficient mice by transferring wt or FcgRIIIA 2/2 bone marrow, but not by transferring FcRg 2/2 bone marrow (11), supports the role of FcgRIV on neutrophils in K/BxN-PA. Activated neutrophils and inflammatory monocytes/macrophages can release myeloperoxidase.…”

“…These three cell types have been reported to be mandatory for K/BxN-PA. K/BxN-PA is, indeed, abrogated in wild-type (wt) mice depleted of monocytes/macrophages (9), depleted of neutrophils (10), or lacking mature neutrophils (11). Based on experiments performed in mast cell-deficient W/W v mice, mast cells are considered necessary for K/BxN-PA (12).…”

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

“…Jnk1 −/− mice had a sufficient number of neutrophils in peripheral blood by flow cytometry (Table S1). To assess the functional role of neutrophils in Jnk1 −/− mice, we used a previously published protocol (28) and transferred WT CD45.1 + BM into CD45.2 + Jnk1 −/− recipients for the first 4 d of arthritis. The transfer did not recapitulate the arthritis seen in WT controls (Fig.…”

“…In addition, the repletion of WT neutrophils did not recapitulate arthritis in JNK1-deficient mice. Although FcγR expression by neutrophils contributes to the generation of arthritis (28), the paucity of JNK1 reported in mature neutrophils (29) suggested that these cells use signaling pathways that are not entirely similar to MCs. Other cell types might also be involved in the attenuated course of arthritis in JNK1-deficient mice, including macrophages.…”