Macrophage dysfunction in cystic fibrosis: nature or nurture?

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the home-ostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respira-tory epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTRis, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitiveto conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophagesby affecting the lung milieu, but the mutations also appear to be directly consequential for intrin-sic macrophage functions. Particular mutations can alter CFTR’s folding, traffic of the proteinto the membrane and function. As such, understanding the intrinsic effects of CFTR mutationrequires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from theprimary defect of CFTR dysfunction/absence. Investigations into CFTR’s role in macrophages haveexploited various models, each with their own advantages and limitations. This review summarizesthese methodologic approaches, discussing their physiological correspondence and highlightingkey findings. The controversy surrounding CFTR-dependent acidification is used as a case studyto highlight difficulties in commensurability across model systems. Recent work in macrophagebiology, including polarization and host–pathogen interaction studies, brought into the context ofCFTR research, offers potential explanations for observed discrepancies between studies. More-over, the rapid advancement of novel gene editing technologies and new macrophage model sys-tems makes this assessment of the field’s models and methodologies timely.Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the home-ostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respira-tory epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTRis, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitiveto conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophagesby affecting the lung milieu, but the mutations also appear to be directly consequential for intrin-sic macrophage functions. Particular mutations can alter CFTR’s folding, traffic of the proteinto the membrane and function. As such, understanding the intrinsic effects of CFTR mutationrequires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from theprimary defect of CFTR dysfunction/absence. Investigations into CFTR’s role in macrophages haveexploited various models, each with their own advantages and limitations. This review summarizesthese methodologic approaches, discussing their physiological correspondence and highlightingkey findings. The controversy surrounding CFTR-dependent acidification is used as a case studyto highlight difficulties in commensurability across model systems. Recent work in macrophagebiology, including polarization and host–pathogen interaction studies, brought into the context ofCFTR research, offers potential explanations for observed discrepancies between studies. More-over, the rapid advancement of novel gene editing technologies and new macrophage model sys-tems makes this assessment of the field’s models and methodologies timely.