Insights into the role of progranulin in immunity, infection, and inflammation

Abstract

PGRN, a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and the host-defense response and therefore, has been widely studied in the fields of infectious diseases, wound healing, tumorigenesis, and neuroproliferative and degenerative diseases. PGRN has also emerged as a multifaceted immune-regulatory molecule through regulating the signaling pathways known to be critical for immunology, especially TNF/TNFR signaling. In this review, we start with updates about the interplays of PGRN with ECM proteins, proteolytic enzymes, inflammatory cytokines, and cell-surface receptors, as well as various pathophysiological processes involved. We then review the data supporting an emerging role of PGRN in the fields of the "Cubic of I", namely, immunity, infection, and inflammation, with special focus on its regulation of autoimmune syndromes. We conclude with insights into the immunomodulating, anti-inflammatory, therapeutic potential of PGRN in treating diseases with an inflammatory etiology in a vast range of medical specialties.

Figure 1.. A diagram illustrates PGRN-mediated signal pathways through its binding receptors.

PGRN binds to TNFR1 and blocks TNF-α-induced inflammatory and apoptotic pathways. The binding of PGRN to TNFR2 may trigger an unknown protective signal cascade and promote Treg differentiation and function. PGRN assists to recruit CpG-ODNs to TLR9 in the endosome to enhance innate immunity and to protect the body from bacterial infection. Interaction between PGRN and Sortilin is important for PGRN trafficking and lysosomal degradation in neurons.