Macrophages from gut-corrected CF mice express human CFTR and lack a pro-inflammatory phenotype

•The cftrtm1unc Tg(FABP-hCFTR) mouse is a commonly-used animal model of CF.•This mouse expresses human CFTR in the gut to prevent fatal intestinal obstruction.•Macrophages from this mouse fail to replicate immune dysfunction seen in patient cells.•We show ectopic expression of human CFTR transgene in macrophages from this CF mouse.•This may help to explain anomalies in the field related to use of this model. 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.