Progranulin: A key player in autoimmune diseases

Abstract

Autoimmune disease encompasses an array of conditions with a variety of presentations and the involvement of multiple organs. Though the etiologies of many autoimmune conditions are unclear, uncontrolled inflammatory immune response is believed to be a major cause of disease development and progression. Progranulin (PGRN), an anti-inflammatory molecule with therapeutic effect in inflammatory arthritis, was identified as an endogenous antagonist of TNFα by competitively binding to TNFR. PGRN exerts its anti-inflammatory activity through multiple pathways, including induction of T differentiation and IL-10 expression and inhibition of chemokine release from macrophages. In addition, the protective role of PGRN has also been demonstrated in osteoarthritis, inflammatory bowel disease, and psoriasis. Intriguingly, PGRN was reported to contribute to development of insulin resistance in high-fat diet induced diabetes. Emerging evidences indicate that PGRN may also be associated with various autoimmune diseases, including systemic lupus erythematous, systemic sclerosis, multiple sclerosis and Sjogren's syndrome. This review summarizes recent studies of PGRN as a novel target molecule in the field of autoimmune disease, and provides updated information to inspire future studies.

Targeting tumor necrosis factor receptors in ankylosing spondylitis

“…36,91 Moreover, PGRN was shown to have protective and therapeutic effects in additional inflammatory disease models, including IBD, psoriasis, diabetes mellitus, systemic lupus erythematosus, and others. 92 A very recent publication has also demonstrated the ability of Atsttrin to inhibit TNF-mediated catabolism in a murine ex vivo model of intervertebral disk degeneration, supporting the protective effect of Atsttrin in TNF-driven inflammatory conditions impacting the axial skeleton. 93 These observations suggest that PGRN might ameliorate inflammatory disease states by simultaneously blocking the proinflammatory effects of TNFR1 and activating protective signaling mediated by TNFR2.…”

“…Notably, the endogenous growth factor progranulin (PGRN) was identified as a natural ligand of TNFRs in 2011 . This ubiquitous molecule has multiple functions, including significant roles in cell proliferation, wound healing, and regulation of immune responses . Interestingly, PGRN functions as a physiological antagonist of TNFR1 and a potent agonist of TNFR2 (with approximately 600‐fold higher binding affinity to TNFR2 than TNF).…”

“…PGRN and Atsttrin, an engineered peptide consisting of the domains and adjacent linker regions of PGRN responsible for interacting with TNFRs, appear to have strong anti‐inflammatory properties and were shown to mediate protective and anabolic effects in mouse models of osteoarthritis and inflammatory arthritis . Moreover, PGRN was shown to have protective and therapeutic effects in additional inflammatory disease models, including IBD, psoriasis, diabetes mellitus, systemic lupus erythematosus, and others . A very recent publication has also demonstrated the ability of Atsttrin to inhibit TNF‐mediated catabolism in a murine ex vivo model of intervertebral disk degeneration, supporting the protective effect of Atsttrin in TNF‐driven inflammatory conditions impacting the axial skeleton .…”

“…36,78,79 This ubiquitous molecule has multiple functions, including significant roles in cell proliferation, wound healing, and regulation of immune responses. [80][81][82][83][84][85][86][87][88][89][90] Interestingly, PGRN functions as a physiological antagonist of TNFR1 and a potent agonist of TNFR2 (with approximately 600-fold higher binding affinity to TNFR2 than TNF). PGRN and Atsttrin, an engineered peptide consisting of the domains and adjacent linker regions of PGRN responsible for interacting with TNFRs, appear to have strong anti-inflammatory properties and were shown to mediate protective and anabolic effects in mouse models of osteoarthritis and inflammatory arthritis.…”

Progranulin autoantibodies in systemic sclerosis and autoimmune connective tissue disorders: A preliminary study

“…Of these, the role of PGRN in inflammation is of substantial interest. Moreover, PGRN is nowadays considered to be a key player in autoimmune diseases . PGRN is a strong anti‐inflammatory mediator acting through the inhibition of TNFR1 and TNFR2 .…”