Progranulin Facilitates Conversion and Function of Regulatory T Cells under Inflammatory Conditions

Abstract

The progranulin (PGRN) is known to protect regulatory T cells (Tregs) from a negative regulation by TNF-α, and its levels are elevated in various kinds of autoimmune diseases. Whether PGRN directly regulates the conversion of CD4+CD25-T cells into Foxp3-expressing regulatory T cells (iTreg), and whether PGRN affects the immunosuppressive function of Tregs, however, remain unknown. In this study we provide evidences demonstrating that PGRN is able to stimulate the conversion of CD4+CD25-T cells into iTreg in a dose-dependent manner in vitro. In addition, PGRN showed synergistic effects with TGF-β1 on the induction of iTreg. PGRN was required for the immunosuppressive function of Tregs, since PGRN-deficient Tregs have a significant decreased ability to suppress the proliferation of effector T cells (Teff). In addition, PGRN deficiency caused a marked reduction in Tregs number in the course of inflammatory arthritis, although no significant difference was observed in the numbers of Tregs between wild type and PGRN deficient mice during development. Furthermore, PGRN deficiency led to significant upregulation of the Wnt receptor gene Fzd2. Collectively, this study reveals that PGRN directly regulates the numbers and function of Tregs under inflammatory conditions, and provides new insight into the immune regulatory mechanism of PGRN in the pathogenesis of inflammatory and immune-related diseases.

Non‐Surgical Periodontal Therapy Reduces Saliva Adipokine and Matrix Metalloproteinase Levels in Periodontitis

“…Progranulin, also called granulin epithelin precursor, is a 593–amino acid secreted growth factor 23 . Progranulin is an adipokine with various biologic functions, such as cell growth regulation, tissue repair, and inflammation modulation 23 , 24 . It has been shown to have anti‐inflammatory and proinflammatory features 25 .…”

The role of progranulin in arthritis

“…In addition, genetic knockout studies indicate that TNF‐α–mediated cardiomyopathy is orchestrated primarily through TNFR1, whereas TNFR2 contributes a protective effect in the pathological processes of TNF‐α–induced heart failure . Moreover, TNFR2 has been shown to have an immunoregulatory effect in regulatory T cell conversion …”

“…The PGRN antibody was also found in several other autoimmune diseases, including vasculitis, systemic lupus erythematosus, RA, and inflammatory bowel diseases . Although PGRN was reported to facilitate the conversion and function of T reg cells under inflammatory conditions, Thurner et al . observed enhanced TNF‐α–induced downregulation of FOXP3 in CD4 + CD25 + T reg cells in the presence of the PGRN antibody.…”

“…PGRN also plays an important role in T reg conversion under inflammatory conditions . T reg cells are known as one of the subsets of CD4 + T cells with immunosuppressive effects, which play a critical role in autoimmune disorders .…”

“…Recent studies revealed that deletion of PGRN led to reduced T reg cell number and reduced T reg cell recruitment to the affected skin in murine models of dermatitis and psoriasis vulgaris models; implementation of PGRN‐derived atsttrin or rPGRN increased T reg cell number in these disease models, as well as in inflammatory arthritis models . Additionally, PGRN was reported to dose dependently facilitate the conversion of CD4 + CD25 − T cells into CD4 + CD25 + FOXP3 + T cells under inflammatory conditions in vitro , and this induction effect can be enhanced in the presence of TGF‐β . Notably, deletion of PGRN resulted in loss of T reg cells’ suppressive effect on T cell proliferation, indicating that PGRN is required for maintaining T reg function as well .…”