Background/Purpose: Progranulin (PGRN) is a growth factor with multiple functions. We recently reported that PGRN and its derived engineered protein Atsttrin directly bound to TNF receptors, inhibited TNF-α activity and exhibited potent anti-inflammatory effect in inflammatory arthritis models (Tang, W., et al, Science, 2011 Apr 22;332(6028):478-484). TNF-α is also known to play a critical role in the pathogenesis of inflammatory bowel disease (IBD), and blockage of TNF-α represents an effective therapeutic option in the treatment of IBD. Thus the objective of this project is 1) to examine the expression profiling of PGRN in the course of IBD, 2) to define the role of endogenous PGRN in IBD, and 3) to determine whether recombinant PGRN or its derivatives represents novel therapeutic interventions for IBD.

Methods: The expression of PGRN in the course of IBD was detected using immunohistochemistry. To elucidate the effects of endogenous PGRN on the initiation and progression of colitis, various colitis models, including DSS- and TNBS-induced colitis model, CD4+CD45Rb^hi T cell transfer model were established with WT and PGRN-deficient mice. To determine the therapeutic effect, recombinant PGRN or Atsttrin at a dosage of 5mg/kg body weight was injected into various experimental colitis models. Body weights were recorded and the colon tissues were collected for histological and immunohistochemical assays.

Results: PGRN was highly expressed in the epithelial cell layer and smooth muscle of colon in WT mice, and its expression was significantly induced in the course of DSS- or TBNS-induced colitis. PGRN KO mice suffered from accelerated body weight loss, and exhibited more severe transmural inflammation with extensive ulceration and necrosis compared to WT mice.  Transfer of PGRN^-/-CD4+ CD45RB^hi T cells into RAG1^-/- recipient mice led to an accelerated onset of disease and to more severe signs of inflammation. In addition, all mice died 35 days after T cell transfer in this group, whereas all mice were still alive following T cell transfer from WT donor mice up to 56 days. These results indicate that CD4+ CD45RB^hi T cells-derived PGRN is critical for the augmented inflammation of IBD. Importantly, injection of recombinant PGRN, or its derived engineered molecule Atsttrin, was able to effectively ameliorate the symptoms of colitis, as revealed by significantly delayed body weight loss and less tissue inflammation. In addition, the application of PGRN restored the survival rate in the T cell transfer model.

Conclusion: PGRN plays a protective role in the pathogenesis of inflammatory bowel disease. PGRN, specially its derived engineered molecules, may be used as new anti-TNF/TNFR therapeutic interventions for inflammatory bowel disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/progranulin-plays-a-protective-role-in-the-pathogenesis-of-inflammatory-bowel-disease/