Hypercholesterolemic LDL receptor-deficient mice mount a neutrophilic response to tuberculosis despite the timely expression of protective immunity

The prevalence of hypercholesterolemia is rising in industrialized and developing countries. We reported previously that host defense against Mtb was impaired by hypercholesterolemia in ApoE(-/-) mice, raising the possibility that people with HC could be more vulnerable to TB. The present study examined whether TB immunity was similarly impaired in a different hypercholesterolemic model, LDL-R(-/-) mice, which developed comparable elevation of total serum cholesterol as ApoE(-/-)mice when fed HC or LC diets. Like ApoE(-/-) mice, LDL-R(-/-) mice had an exaggerated lung inflammatory response to Mtb with increased tissue necrosis. Inflammation, foamy macrophage formation, and tissue necrosis in LDL-R(-/-) mice increased with the degree of hypercholesterolemia. Unlike ApoE(-/-) mice, LDL-R(-/-) mice fed a HC diet mounted a timely and protective adaptive immune response that restricted mycobacterial replication comparably with WT mice. Thus, ApoE(-/-) and LDL-R(-/-) mice share a cholesterol-dependent hyperinflammatory TB phenotype but do not share the impairment of adaptive immunity found in ApoE(-/-) mice. The impact of hypercholesterolemia on TB immunity is more complex than appreciated by total cholesterol alone, possibly reflecting the different functional effect of specific lipoprotein particles.