Abstract
Lipocalin-2 is a constituent of the neutrophil secondary granules and is expressed de novo by macrophages and epithelium in response to inflammation. Lipocalin-2 acts in a bacteriostatic fashion by binding iron-loaded siderophores required for bacterial growth. Mycobacterium tuberculosis (M.tb) produces siderophores that can be bound by lipocalin-2. The impact of lipocalin-2 in the innate immune response toward extracellular bacteria has been established whereas the effect on intracellular bacteria, such as M.tb, is less well-described. Here we show that lipocalin-2 surprisingly confers a growth advantage on M.tb in the early stages of infection (3 weeks post-challenge). Using mixed bone marrow chimeras, we demonstrate that lipocalin-2 derived from granulocytes, but not from epithelia and macrophages, leads to increased susceptibility to M.tb infection. In contrast, lipocalin-2 is not observed to promote mycobacterial growth at later stages of M.tb infection. We demonstrate co-localization of granulocytes and mycobacteria within the nascent granulomas at week 3 post-challenge, but not in the consolidated granulomas at week 5. We hypothesize that neutrophil-derived lipocalin-2 acts to supply a source of iron to M.tb in infected macrophages within the immature granuloma, thereby facilitating mycobacterial growth.
Highlights
Adaptive immunity against Mycobacterium tuberculosis (M.tb) is well-described, whereas the role of the innate immune response that acts at the early stages of infection is not fully defined
To evaluate the lipocalin-2 expression pattern following M.tb infection, Lcn2 gene expression was measured in the lungs of WT mice during the growth/primary stage (3 weeks) and the post-peak chronic stage (5 weeks) after aerosol-infection with M.tb relative to that of uninfected WT mice
The innate immune response is primarily important at the early stages of infection, previous in vivo tuberculosis studies have focused on the effect of lacking lipocalin-2 at later stages of infection, when the adaptive immune response dominates [33]
Summary
Adaptive immunity against Mycobacterium tuberculosis (M.tb) is well-described, whereas the role of the innate immune response that acts at the early stages of infection is not fully defined. Lipocalin-2 is an innate immune protein, known as neutrophil gelatinase-associated lipocalin (NGAL), originally identified as a major constituent of the neutrophil secondary granules [1, 2]. Lipocalin-2 is produced exclusively at the myelocyte and metamyelocyte stages of granulopoiesis in the bone marrow and stored in the secondary granules [3]. Following the release of neutrophils from bone marrow, lipocalin-2 can be exocytosed from the pre-formed granules. In mice [8, 9], but not in humans [10], lipocalin-2 is produced in the liver as an acute phase-protein
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