Lipocalin-2 functions as inhibitor of innate resistance to mycobacterium tuberculosis

Sara Louise Dahl; Joshua S. Woodworth; Christian Johann Lerche; Elisabeth Præstekjær Cramer; Pia Rude Nielsen; Claus Moser; Allan Randrup Thomsen; Niels Borregaard; Jack Bernard Cowland

doi:10.3389/fimmu.2018.02717

Lipocalin-2 functions as inhibitor of innate resistance to mycobacterium tuberculosis

Sara Louise Dahl, Joshua S. Woodworth, Christian Johann Lerche, Elisabeth Præstekjær Cramer, Pia Rude Nielsen, Claus Moser, Allan Randrup Thomsen, Niels Borregaard, Jack Bernard Cowland^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

9 Citationer (Scopus)

50 Downloads (Pure)

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.

Originalsprog	Engelsk
Artikelnummer	02717
Tidsskrift	Frontiers in Immunology
Vol/bind	9
Antal sider	16
ISSN	1664-3224
DOI	https://doi.org/10.3389/fimmu.2018.02717
Status	Udgivet - 26 nov. 2018

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10.3389/fimmu.2018.02717Licens: CC BY

Lipocalin-2 Functions as Inhibitor of Innate Resistance to Mycobacterium tuberculosisForlagets udgivne version, 3,51 MBLicens: CC BY

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title = "Lipocalin-2 functions as inhibitor of innate resistance to mycobacterium tuberculosis",

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.",

keywords = "24p3, innate immunity, iron metabolism, Lcn2, Mycobacterium tuberculosis, neutrophils, NGAL",

author = "Dahl, {Sara Louise} and Woodworth, {Joshua S.} and Lerche, {Christian Johann} and Cramer, {Elisabeth Pr{\ae}stekj{\ae}r} and Nielsen, {Pia Rude} and Claus Moser and Thomsen, {Allan Randrup} and Niels Borregaard and Cowland, {Jack Bernard}",

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TY - JOUR

T1 - Lipocalin-2 functions as inhibitor of innate resistance to mycobacterium tuberculosis

AU - Dahl, Sara Louise

AU - Woodworth, Joshua S.

AU - Lerche, Christian Johann

AU - Cramer, Elisabeth Præstekjær

AU - Nielsen, Pia Rude

AU - Moser, Claus

AU - Thomsen, Allan Randrup

AU - Borregaard, Niels

AU - Cowland, Jack Bernard

PY - 2018/11/26

Y1 - 2018/11/26

N2 - 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.

AB - 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.

KW - 24p3

KW - innate immunity

KW - iron metabolism

KW - Lcn2

KW - Mycobacterium tuberculosis

KW - neutrophils

KW - NGAL

U2 - 10.3389/fimmu.2018.02717

DO - 10.3389/fimmu.2018.02717

M3 - Journal article

C2 - 30534124

AN - SCOPUS:85057378323

SN - 1664-3224

VL - 9

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 02717

ER -

Lipocalin-2 functions as inhibitor of innate resistance to mycobacterium tuberculosis

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