Fk506-binding protein 11, a plasma cell-specific protein folding catalyst, is increased in pulmonary fibrosis

Rationale:

We have recently identified the chaperone and peptidyl-prolyl isomerase FK506-binding protein 10 (FKBP10) as a profibrotic mediator in idiopathic pulmonary fibrosis (IPF). In this study, we sought to assess expression, localization, regulation and function of a related protein, FKBP11, in lung fibrosis.

Methods:

Expression of FKBP11 in lung tissue was analysed during the onset and resolution of bleomycin-induced lung fibrosis (up to day 56) in C57BL/6N mice, as well as in lungs from two independent IPF cohorts using Western Blot analysis and examination of DNA-microarray data. Immunofluorescence of IPF-sections was used to determine the cell type expressing FKBP11 and to quantify FKBP11-positive cells in IPF tissue sections relative to donor and chronic obstructive pulmonary disease (COPD) tissue. In addition, FKBP11 expression and regulation was assessed in a B Cell line and antibody-producing cell lines. Finally, B cell to plasma cell transdifferentiation of Peripheral Blood Mononuclear Cells (PBMCs) and knockdown experiments of hybridoma cells were performed to investigate the function of FKBP11.

Results:

FKBP11 expression was increased in the fibrotic phase of bleomycin-induced lung fibrosis as well as two independent IPF cohorts. Immunofluorescent stainings in IPF tissue sections confirmed these observations showing elevated numbers of FKBP11 positive cells in contrast to healthy donor and COPD. Costainings with markers for hematopoietic lineage demonstrated specific expression of FKBP11 in CD45-/CD20-/CD38+/CD27+/CD138+ plasma cells producing mainly Immunoglobulin A and G. Antibody-producing cell lines displayed strong expression of FKBP11 confirming plasma cell specificity of FKBP11. What's more, induction of ER stress in a B Cell line using tunicamycin resulted in an increase of FKBP11. B Cell transdifferentiation led to an upregulation of FKBP11, whereas knockdown resulted in reduced viability and antibody secretion.

Conclusions:

The protein folding catalyst FKBP11 is increased in IPF, specifically localizes to plasma cells in the lung and is regulated by ER stress. These results suggest a function of FKBP11 in plasma cell biology and B cell differentiation and support the autoimmune hypothesis in IPF.