Abstract
The respiratory tract is constantly exposed to pathogens that require iron for proliferation and virulence. Pulmonary iron levels are increased in several lung diseases and associated with increased susceptibility to infections. However, regulation of lung iron homeostasis and its cross talk to pulmonary immune responses are largely unexplored. Here we investigated how increased lung iron levels affect the early pulmonary inflammatory response. We induced acute local pulmonary inflammation via aerosolized LPS in a mouse model of hereditary hemochromatosis type 4 (Slc40a1C326S/C326S), which is hallmarked by systemic and pulmonary iron accumulation, specifically in alveolar macrophages. We show that Slc40a1C326S/C326S mice display a mild attenuation in the LPS-induced pulmonary inflammatory response, with a reduced upregulation of some pro-inflammatory cytokines and chemokines. Despite mildly reduced cytokine levels, there is no short-term impairment in the recruitment of neutrophils into the bronchoalveolar space. These data suggest that increased pulmonary iron levels do not strongly alter the acute inflammatory response of the lung.
Highlights
Iron is essential for the proliferation and virulence of most pathogens
We have previously reported that iron accumulates in the lung of Slc40a1C326S/C326S mice, in alveolar macrophages, which play a key role in the pulmonary inflammatory response against inhaled pathogens (Neves et al, 2017)
Our results show that increased systemic and/or lung iron levels cause a mild attenuation in the pulmonary acute inflammatory response, without significantly affecting the LPS-induced recruitment of neutrophils to the alveolar space
Summary
Iron is essential for the proliferation and virulence of most pathogens. To reduce iron availability for extracellular pathogens in the plasma, the host sequesters iron intracellularly in reticuloendothelial macrophages (Ganz and Nemeth, 2009). Since ferroportin is predominantly expressed in cells that handle major iron flows, such as macrophages and duodenal enterocytes, hepcidin binding causes a decrease in iron release from these iron-exporting cell types and hypoferremia develops. Ferroportin expression in macrophages is downregulated at the transcriptional level via TLR4- and TLR2/TLR6- signaling pathways (Liu et al, 2005; Peyssonnaux et al, 2006; Guida et al, 2015). The resulting decrease in iron export reduces plasma iron levels independently of hepcidin (Guida et al, 2015). These responses reveal an active and important cross-talk between the control of systemic iron metabolism and immune responses and demonstrate how iron homeostasis is altered by inflammation. The impact of altered iron homeostasis on the immune response is largely unexplored
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