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Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition

Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition
Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition
The natural resistance-associated macrophage protein 1, Slc11a1, is a phagolysosomal transporter for protons and divalent ions including iron that confers host protection against diverse intracellular pathogens including Salmonella. We investigated and compared the regulation of iron homeostasis and immune function in RAW264.7 murine phagocytes stably transfected with non-functional Slc11a1 and functional Slc11a1 controls in response to an infection with Salmonella enterica serovar Typhimurium. We report that macrophages lacking functional Slc11a1 displayed an increased expression of transferrin receptor 1, resulting in enhanced acquisition of transferrin-bound iron. In contrast, cellular iron release mediated via ferroportin 1 was significantly lower in Salmonella-infected Slc11a1-negative macrophages in comparison with phagocytes bearing Slc11a1. Lack of Slc11a1 led to intracellular persistence of S.?enterica serovar Typhimurium within macrophages, which was paralleled by a reduced formation of nitric oxide, tumour necrosis factor-alpha and interleukin-6 in Slc11a1-negative macrophages following Salmonella infection, whereas interleukin-10 production was increased. Moreover, Slc11a1-negative phagocytes exhibited higher cellular iron content, resulting in increased iron acquisition by intracellular Salmonella. Our observations indicate a bifunctional role for Slc11a1 within phagocytes. Slc11a restricts iron availability, which first augments pro-inflammatory macrophage effector functions and second concomitantly limits microbial iron access.
1462-5814
1365-1381
Nairz, Manfred
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Fritsche, Gernot
bc86d130-0ef3-4061-9212-532031dcc8f4
Crouch, Marie-Laure V.
427b1d0d-a2bd-4376-a68e-47ab5976081c
Barton, Howard C.
5dfb4e1a-d559-4b58-9036-31de1e6c9ad8
Fang, Ferric C.
d7a3f05f-37e0-46ce-ae84-5d3234a29590
Weiss, Günter
46b72980-1b23-41d8-b5af-0396e5ed3316
Nairz, Manfred
2ebf9113-8a46-4d35-b586-825a0e05a1aa
Fritsche, Gernot
bc86d130-0ef3-4061-9212-532031dcc8f4
Crouch, Marie-Laure V.
427b1d0d-a2bd-4376-a68e-47ab5976081c
Barton, Howard C.
5dfb4e1a-d559-4b58-9036-31de1e6c9ad8
Fang, Ferric C.
d7a3f05f-37e0-46ce-ae84-5d3234a29590
Weiss, Günter
46b72980-1b23-41d8-b5af-0396e5ed3316

Nairz, Manfred, Fritsche, Gernot, Crouch, Marie-Laure V., Barton, Howard C., Fang, Ferric C. and Weiss, Günter (2009) Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition. Cellular Microbiology, 11 (9), 1365-1381. (doi:10.1111/j.1462-5822.2009.01337.x).

Record type: Article

Abstract

The natural resistance-associated macrophage protein 1, Slc11a1, is a phagolysosomal transporter for protons and divalent ions including iron that confers host protection against diverse intracellular pathogens including Salmonella. We investigated and compared the regulation of iron homeostasis and immune function in RAW264.7 murine phagocytes stably transfected with non-functional Slc11a1 and functional Slc11a1 controls in response to an infection with Salmonella enterica serovar Typhimurium. We report that macrophages lacking functional Slc11a1 displayed an increased expression of transferrin receptor 1, resulting in enhanced acquisition of transferrin-bound iron. In contrast, cellular iron release mediated via ferroportin 1 was significantly lower in Salmonella-infected Slc11a1-negative macrophages in comparison with phagocytes bearing Slc11a1. Lack of Slc11a1 led to intracellular persistence of S.?enterica serovar Typhimurium within macrophages, which was paralleled by a reduced formation of nitric oxide, tumour necrosis factor-alpha and interleukin-6 in Slc11a1-negative macrophages following Salmonella infection, whereas interleukin-10 production was increased. Moreover, Slc11a1-negative phagocytes exhibited higher cellular iron content, resulting in increased iron acquisition by intracellular Salmonella. Our observations indicate a bifunctional role for Slc11a1 within phagocytes. Slc11a restricts iron availability, which first augments pro-inflammatory macrophage effector functions and second concomitantly limits microbial iron access.

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Published date: September 2009

Identifiers

Local EPrints ID: 143337
URI: http://eprints.soton.ac.uk/id/eprint/143337
ISSN: 1462-5814
PURE UUID: 9a53513f-1b4c-4984-936d-b8365fce04da

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Date deposited: 08 Apr 2010 12:54
Last modified: 14 Mar 2024 00:43

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Contributors

Author: Manfred Nairz
Author: Gernot Fritsche
Author: Marie-Laure V. Crouch
Author: Ferric C. Fang
Author: Günter Weiss

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