Bile Salt-Stimulated Lipase Plays an Unexpected Role in Arthritis Development in Rodents

Susanne Lindquist,Olle Hernell,Eva-Lotta Andersson,Lennart Lundberg,Oliver Frey

doi:10.1371/journal.pone.0047006

Susanne Lindquist, Olle Hernell + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0047006

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Journal: PLoS ONE	Publication Date: Oct 11, 2012
Citations: 51	License type: CC BY 4.0

Affiliation: Umeå University

Abstract

ObjectiveThe present study aimed to explore the hypothesis that bile salt-stimulated lipase (BSSL), in addition to being a key enzyme in dietary fat digestion during early infancy, plays an important role in inflammation, notably arthritis.MethodsCollagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rodents are commonly used experimental models that reproduce many of the pathogenic mechanisms of human rheumatoid arthritis, i.e. increased cellular infiltration, synovial hyperplasia, pannus formation, and erosion of cartilage and bone in the distal joints. We used the CIA model to compare the response in BSSL wild type (BSSL-WT) mice with BSSL-deficient ‘knock-out’ (BSSL-KO) and BSSL-heterozygous (BSSL-HET) littermates. We also investigated if intraperitoneal injection of BSSL-neutralizing antibodies affected the development or severity of CIA and PIA in mice and rats, respectively.ResultsIn two consecutive studies, we found that BSSL-KO male mice, in contrast to BSSL-WT littermates, were significantly protected from developing arthritis. We also found that BSSL-HET mice were less prone to develop disease compared to BSSL-WT mice, but not as resistant as BSSL-KO mice, suggesting a gene-dose effect. Moreover, we found that BSSL-neutralizing antibody injection reduced both the incidence and severity of CIA and PIA in rodents.ConclusionOur data strongly support BSSL as a key player in the inflammatory process, at least in rodents. It also suggests the possibility that BSSL-neutralizing agents could serve as a therapeutic model to reduce the inflammatory response in humans.

Highlights

Collagen-induced arthritis (CIA) in mice is a commonly used experimental model that reproduces many of the pathogenic features of human rheumatoid arthritis (RA), i.e. increased infiltration of neutrophilic granulocytes, synovial hyperplasia, pannus formation, and erosion of cartilage and bone in the distal joints
Screening of bile salt-stimulated lipase (BSSL) genotypes was performed by polymerase chain reaction (PCR) as previously described [25] and major histocompatibility complex (MHC) genotyping was performed using microsatellite marker D17mit230 [27]
The most striking result was detected in BSSL deficient male mice, which were almost completely protected from arthritis, and developed significantly lower mean arthritis scores compared to their BSSL wild type (BSSL-WT) male littermates (p,0.01 from day 28 onwards; Fig. 1A)

Summary

Introduction

Collagen-induced arthritis (CIA) in mice is a commonly used experimental model that reproduces many of the pathogenic features of human rheumatoid arthritis (RA), i.e. increased infiltration of neutrophilic granulocytes, synovial hyperplasia, pannus formation, and erosion of cartilage and bone in the distal joints. BSSL is primarily recognized as a lipolytic enzyme that facilitates digestion and absorption of dietary fat. It has broad specificity and hydrolyzes a variety of different substrates [1,2,3]. BSSL is expressed in the exocrine pancreas and secreted into the intestinal lumen in all species far investigated, including those devoid of pancreatic triglyceride lipase [4,5]. Besides BSSL an oncofetal variant termed feto-acinar pancreatic protein (FAPP), has been described. This form is poorly secreted and exclusively expressed in human fetal and diseased pancreas, but to our knowledge not in other species, or in pancreas of healthy adults [6]

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