Background/Purpose: Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein produced mainly by cells of the mesenchymal lineage. The function of FSTL1 is still unclear, but it appears to play roles in the regulation of cell proliferation, differentiation, and organ development. We have previously shown that FSTL1 is an important mediator in the pathogenesis of arthritis and other systemic autoimmune diseases, and that FSTL1 expression is induced in vitro by Toll-like receptor 4 signaling. The aim of the current study was to determine the molecular mechanism by which FSTL1 promotes inflammation. 

Methods: The level of FSTL1 in the sera of patients with sepsis was measured by ELISA. To further test the contribution of FSTL1 to inflammatory response in vivo, we utilized a model of endotoxin shock in FSTL1 null mice recently generated in our laboratory. Serum IL-1β  levels were determined by ELISA. FSTL1 binding to monocytes/macrophages and its intracellular trafficking were assessed by confocal microscopy. The expression of inflammasome components was evaluated by quantitative RT-PCR and Western blotting. To test whether FSTL1 plays a role in cellular energy production, we performed gene expression microarray analysis on ST2 stromal cells in which FSTL1 expression was knocked down using lentiviral short hairpin RNA.  Enzymatic assays and in situ gel staining were used to measure the activity of mitochondrial electron transport chain complexes. ATP determination in cell lysates was performed using a colorimetric assay. 

Results: We found that the sera of septic patients contained elevated levels of FSTL1 compared to healthy controls. In a mouse model of sepsis, animals deficient in FSTL-1 exhibited a significantly lower IL-1β response than did control mice. Our results indicate that FSTL1 may function to augment cellular responses to infectious organisms or various other noxious stimuli. We found that FSTL1 was able to gain access to the intracellular space of cells that do not normally express FSTL1, such as monocytes/macrophages, either via increased plasma membrane permeability or via an unidentified cell surface receptor. We found intracellular FSTL1 associated with mitochondria, where it enhanced ATP production.  FSTL1 also increased NLRP3 and pro-caspase-1 expression. Together, these promote activation of the NLRP3 inflammasome and secretion of IL-1β, one of the key regulators of inflammation.

Conclusion: Here, we demonstrate that FSTL1 has the ability to enhance the responses of monocytes/macrophages to inflammatory signals. The results reveal a novel mechanism by which FSTL1 acts in inflammation. Our work suggests that the neutralization of FSTL1 activity may be useful in the treatment of various inflammatory conditions.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-pro-inflammatory-signaling-pathway-regulated-by-follistatin-like-protein-1/