Fibrinogen-Like Protein 1 Serves as an Anti-Inflammatory Agent for Collagen-Induced Arthritis Therapy in Mice

Abstract

Fibrinogen-like protein 1 (FGL1) was recently identified as a major ligand of lymphocyte-activation gene-3 (LAG-3) on activated T cells and serves as an immune suppressive molecule for regulation of immune homeostasis. However, whether FGL1 has therapeutic potential for use in the T cell-induced the autoimmune disease, rheumatoid arthritis (RA), is still unknown. Here, we attempted to evaluate the effect of FGL1 protein on arthritis progression. We also evaluated potential adverse events in a collagen-induced arthritis (CIA) mouse model. We first confirmed that soluble Fgl1 protein could specifically bind to surface Lag-3 receptor on 3T3-Lag-3 cells and further inhibit interleukin (IL-2) and interferon gamma (IFNγ) secretion from activated primary mouse T cells by 95% and 43%, respectively. Intraperitoneal administration of Fgl1 protein significantly decreased the inflammatory cytokine level (i.e., IL-1β and IL-6) in local paw tissue, and prevented joint inflammation, cellular infiltration, bone deformation and attenuated collagen-induced arthritis progression in vivo. We further demonstrated that exogenous Fgl1 does not cause obvious adverse events during treatment by monitoring body weight and liver weight, and assessing the morphology of several organs (i.e., heart, liver, spleen, lung and kidney) by pathological studies. We expect that Fgl1 protein may be suitable to serve as a potential therapeutic agent for treatment of RA or even other types of T cell-induced autoimmune or inflammatory diseases in the future.

The role of fibrinogen-like protein 1 in immune escape and tumor growth mechanism of Warthin’s tumor

“…Normally, FGL1 is secreted by hepatocyte cells of the liver. 19,20 However, it is possible that WT cells also produce FGL1. 16 According to Qian et al, 16 the gene that produces FGL1 is located on human chromosome 8p22 and is present in all human somatic cells, although normally only hepatocyte cells express it.…”

“…19 Under normal conditions, FGL1 is physiologically secreted by hepatocyte cells. 19,20 However, FGL1 was also highly expressed in various tumors such as lung, prostate, melanoma, colorectal, breast, and brain tumors. 16,19 This high expression of FGL1 in tumor cells contributes to the growth and development of neoplasms causes host lymphocyte cells (Tumor Infiltrating lymphocytes) to become cell exhausted, a condition in which lymphocytes lose their ability to kill tumor cells.…”

Xue-Jie-San restricts ferroptosis in Crohn’s disease via inhibiting FGL1/NF-κB/STAT3 positive feedback loop

“…Above evidences show a controversial role of FGL1 in inflammatory diseases. Deficiency of FGL1 can induce spontaneous dermatitis in gene knockout mice, and supplement of FGL1 recombinant protein improves collagen-induced arthritis ( Wang et al, 2019 ; Lin et al, 2021 ). These evidences verify the function of FGL1 regulating autoimmunity and immune homeostasis via binding to lymphocyte-activation gene 3 (LAG-3) to inhibit T cell activation ( Wang et al, 2019 ; Lin et al, 2021 ).…”

“…Deficiency of FGL1 can induce spontaneous dermatitis in gene knockout mice, and supplement of FGL1 recombinant protein improves collagen-induced arthritis ( Wang et al, 2019 ; Lin et al, 2021 ). These evidences verify the function of FGL1 regulating autoimmunity and immune homeostasis via binding to lymphocyte-activation gene 3 (LAG-3) to inhibit T cell activation ( Wang et al, 2019 ; Lin et al, 2021 ). However, on the other hand, inhibition of LAG-3 initiates intestinal inflammation by disturbing the immunosuppressive function of Treg cells ( Bauché et al, 2018 ).…”

The impact of exosomes derived from distinct sources on rheumatoid arthritis

“…Fibrinogen-like protein 1 (FGL1) is a member of the fibrinogen family and can be recognized as an immune checkpoint target through an immune escape mechanism ( 27 ). FGL1 functions as an anti-inflammatory agent in collagen-induced RA ( 28 ). Subsequent investigations have demonstrated that FGL1 contained in MSCs-Exo exhibits therapeutic effects on RA without significant adverse reactions.…”