Absence of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling protects against collagen-induced arthritis

Abstract

ObjectiveComprehending the mechanisms that regulate activation of autoreactive T cells and B cell antibody production is fundamental for understanding the breakdown in self-tolerance and development of autoimmunity. Here we studied the role of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling in the pathogenesis of collagen-induced arthritis (CIA).MethodsCIA was induced in mice lacking Flt3L (Flt3L−/−) and wild-type (WT) littermates (C57/BL6, 8–10 weeks old). Mice were killed in the initial phase (acute phase: experiment 1) and late phase (chronic phase: experiment 2) of the disease. Arthritis severity was assessed using a semiquantitative scoring system (0–4), and histological analysis of cellular infiltration, cartilage destruction and peptidoglycan loss was performed. Phenotypic and functional analysis of T and B cells, FoxP3 expression, activation and lymphocyte costimulatory markers, and cytokine production were performed ex vivo by flow cytometry in lymph nodes. Serum collagen type II (CII)-specific antibodies were measured by ELISA.ResultsFlt3L−/− mice showed a marked decrease in clinical arthritis scores and incidence of arthritis in both acute and chronic phases of CIA compared with WT mice. Moreover, decreased synovial inflammation and joint destruction was observed. Both the magnitude and quality of T cell responses were altered in Flt3L−/−. In the acute phase, the amount of CII-specific IgG2a antibodies was lower in Flt3L−/− than WT mice.ConclusionsThese results strongly suggest a role for Flt3L signalling in the development of arthritis.

Editorial: Flt3 ligand—friend or foe?

“…These findings contradict previous data, showing that Flt3L KO mice are protected from developing arthritis [5]. What could be the explanation for these conflicting results?…”

“…Ramos et al [3] also demonstrated that peripheral blood monocytes not only appear to be the primary source of Flt3L in RA patients but also express the highest levels of the Flt3L receptor (Flt3/CD135), suggesting an autocrine regulation. Flt3L KO mice are protected from developing arthritis in a CIA model and have lower levels of proinflammatory cytokines, CII-specific IgG2a antibodies, and decreased synovial inflammation [5].…”

A Truncated IL‐17RC Peptide Ameliorates Synovitis and Bone Destruction of Arthritic Mice

“…Induction of CIA : In the first CIA model, 100 μL chick type II collagen dissolved in 0.01 m acetic acid to a concentration of 4 mg mL −1 was emulsified in an equal volume of Freund's complete adjuvant and administered intradermally at the base of the tail of C57BL/6N mice (15 mice per group). On day 21, a booster emulsion prepared with type II collagen and Freund's incomplete adjuvant was administered intradermally near the primary injection site . The truncated IL‐17RC peptide (150 μg, 100 μL) was injected intraperitoneally three times per week on day 14 after the initial immunization whereas PBS was used as a control.…”

“…The hind‐paw was scored every day and the swelling was measured every 3 d. On day 37 after the first immunization, mice were anesthetized. The clinical scores were assigned as previously described …”

Impaired signaling through the Fms-like tyrosine kinase 3 receptor increases osteoclast formation and bone damage in arthritis

“…Accordingly, local knee exposure to Flt3L aggravates arthritis in mice [30]. Furthermore, Flt3L-deficient mice are protected against collagen-induced arthritis, and blockade of Flt3 signaling reduces the severity of antigen-induced arthritis in mice [34,35].…”