Progranulin Controls Sepsis via C/EBPα-RegulatedIl10Transcription and Ubiquitin Ligase/Proteasome-Mediated Protein Degradation

Abstract

Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes including cellular proliferation, neuron development and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. Here we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production. Conversely, administration of recombinant PGRN decreases the susceptibility of PGRN-deficient mice to LPS-induced endotoxemic shock and augments IL-10 production by LPS-activated macrophages in a TNFR-dependent manner. Molecular analysis reveals a direct role of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) in PGRN-regulated IL-10 expression. C/EBPα–deficient macrophages produce less IL-10 in response to LPS. Further, mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock. Lastly, the defective IL-10 production by PGRN-deficient cells is primarily due to reduced C/EBPα protein stability via the E3 ubiquitin conjugating enzyme E6AP and proteasome-mediated degradation. This study provides the first evidence that PGRN is a non-redundant regulator of systemic inflammation via modulating the levels and activity of C/EBPα, IL-10 and the ubiquitin-proteasome proteolysis pathway. The results bear strong and profound implications for PGRN-insufficiency and its mutation-associated systemic and organ-specific inflammatory human diseases.

Anti-inflammatory Activity of MTL-CEBPA, a Small Activating RNA Drug, in LPS-Stimulated Monocytes and Humanized Mice

“…They also identified that mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock. 25 In our study, production of IL-10 increased in LPS-challenged mice treated with MTL-CEBPA compared with an LPS-challenged control group, further supporting the previously published data, and showing that IL-10 is an important downregulating mechanism in NLRP3 inflammasome-driven inflammation. 55 …”

“…Yan et al. 25 have shown in a similar LPS-induced septic shock model that C/EBPα-deficient macrophages produce less IL-10 in response to LPS and that this process is regulated by the downstream pleiotropic protein progranulin. They also identified that mice deficient in C/EBPα in hematopoietic cells are highly vulnerable to LPS-induced septic shock.…”

Foxo4‐ and Stat3‐dependent IL‐10 production by progranulin in regulatory T cells restrains inflammatory arthritis

“…Although there are many cellular sources of IL‐10, there are a limited number of studies that have defined the lineage‐specific requirements for Il10 transcription. In macrophages, the transcription factor C/EBPα is involved in LPS‐induced IL‐10 production (49). In CD4 + T cells, the transcription factor GATA‐3 is associated with the remodeling and stabilization of Il10 locus required for Il10 transcription (50).…”

Serum progranulin levels are associated with frailty in middle-aged individuals

“…In both cases, we detected associations between serum progranulin levels and frailty as determined by the FRAIL scale (Table 2 and S1 Table). Progranulin levels are regulated by inflammation [36,37] as well as by lysosomal transcription factors [38,39]. Since inflammation and lysosome biology are both tightly linked with aging [40,41], it is possible that these processes contribute both to the development of frailty and to the increased serum progranulin levels.…”