Progranulin as a Potential Therapeutic Target in Immune-Mediated Diseases

Abstract

Progranulin (PGRN), a secretory glycoprotein consisting of 593 amino acid residues, is a key actor and regulator of multiple system functions such as innate immune response and inflammation, as well as tissue regeneration. Recently, there is emerging evidence that PGRN is protective in the development of a variety of immune-mediated diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) by regulating signaling pathways known to be critical for immunology, particularly the tumor necrosis factor alpha/TNF receptor (TNF-α/TNFR) signaling pathway. Whereas, the role of PGRN in psoriasis, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is controversial. This review summarizes the immunological functions of PGRN and its role in the pathogenesis of several immune-mediated diseases, in order to provide new ideas for developing therapeutic strategies for these diseases.

Keywords: PGRN; TNF-α; TNFR; immune-mediated diseases; therapeutic.

Graphical abstract

Figure 1

The structure, source and intervention of PGRN in the autoimmune system. The architecture of PGRN is made up of 7.5 cysteine-rich motif and mainly distributes in various cell lines. Some microRNAs specifically stimulate or inhibit PGRN activation. The SLPI and apolipoprotein A1 can bind to it to protect it against proteolytic degradation by MMP-9, MMP-12, MMP-14, neutrophil elastase, and PRTN3. Atsttrin: an engineered protein consists of the FAC domain of PGRN.

Figure 2

Immunological functions of PGRN. Four main immunological functions of PGRN: Pro-inflammatory: PGRN can be subjected to degradation into GRN fragments by MMP-9, MMP-12, MMP-14, neutrophil elastase, and PRTN3, GRNs stimulate secretion of IL-8 by epithelium cells in MS; Anti-inflammatory: PGRN binds to TNFR1 and activates ERK1/2 and PI3K/AKT pathways to inhibit TNF-α activated NF-κB inflammatory pathway which promotes the release of pro-inflammatory cytokines, mainly IL-6; PGRN selectively inhibits expression and release of CXCL9 and CXCL10 induced by TNF-α in a TNFR1 dependent manner; Combination of PGRN and TNFR2 will ameliorate chronic inflammatory disorders via FOXO4–STAT3-dependent IL-10 production in Tregs; Induce chondrogenesis and cartilage repair: PGRN activates the ERK/JunB signaling pathways; PGRN may inhibit cartilage loss bone resorption mediated by NF-κB pathway in a TNFR1-dependent manner; Inhibiting ADAMTS-7/ADAMTS-12–mediated COMP degradation and TNF-α-induced ADAMTS-7/ADAMTS-12 expression; Regulating of TLR9 signaling pathway.