Abstract
Macrophages represent prominent immune orchestrators of cystic fibrosis (CF) inflammation and, as such, are an ever-increasing focus of CF research with several reports of intrinsic immune dysfunction related to loss of CFTR activity in macrophages themselves. Animal models of CF have contributed, in no small part, to a deepening of our understanding of the pathophysiology of the disease and towards therapeutic development. A commonly-used animal model in CF research is the Cftrtm1Unc Tg(FABP-hCFTR) mouse, which displays gut-specific expression of a human CFTR transgene in order to rescue the high rate of early mortality in Cftr-null mice associated with severe intestinal obstruction. We find significant variation in the response to inflammatory challenge of patient macrophages and cells derived from the Cftrtm1Unc Tg(FABP-hCFTR) mouse and show that macrophages derived from this mouse exhibit aberrant expression of human CFTR. This may contribute to the absence of inflammatory changes in this model.
Highlights
Chronic airway inflammation underpins the progression of cystic fibrosis (CF) lung disease and is a major focus of CF research and an important therapeutic target
Expression of proinflammatory Il1β, as measured by Quantitative real time PCR (qRT-PCR), remained highly upregulated after 24 stimulation with LPS compared to untreated controls but there was no significant difference in the magnitude of this upregulation between CF and WT bone-marrow derived macrophages (BMDMs), expression of the human orthologue was significantly elevated in patient monocyte-derived macrophages (MDMs) at the same time point relative to non-CF controls (Fig. 1C)
[m5G;November 16, 2021;14:0] Journal of Cystic Fibrosis xxx (xxxx) xxx protein in lysates from BMDMs derived from Cftrtm1Unc Tg(FABP-hCFTR) mice or WT littermates and from 16HBEs was detected by western blot. β-Actin protein detection is shown as loading control
Summary
Chronic airway inflammation underpins the progression of CF lung disease and is a major focus of CF research and an important therapeutic target. One CF mouse model designed to offset this issue is the Cftrtm1Unc Tg(FABP-hCFTR) mouse which displays gut-specific expression of a human CFTR transgene, driven by the intestinal fatty acid-binding protein 2 (FABP2) promoter [9]. This allows for survival to maturity with correction of the CF phenotype restricted largely to the gut and this model is subsequently in widespread use in studying the effects of CFTR loss on other systems [10,11,12,13,14]. Together these data suggest that this widely used mouse model has significant limitations in the study of CF associated inflammation
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