The heme scavenger hemopexin protects against lung injury during aspergillosis by mitigating release of neutrophil extracellular traps
Ganlin Qu, Henrique A.L. Ribeiro, Angelica L. Solomon, Luis Sordo Vieira, Yana Goddard, Nickolas G. Diodati, Arantxa V. Lazarte, Matthew Wheeler, Reinhard Laubenbacher, Borna Mehrad
Ganlin Qu, Henrique A.L. Ribeiro, Angelica L. Solomon, Luis Sordo Vieira, Yana Goddard, Nickolas G. Diodati, Arantxa V. Lazarte, Matthew Wheeler, Reinhard Laubenbacher, Borna Mehrad
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Research Article Immunology Infectious disease Pulmonology

The heme scavenger hemopexin protects against lung injury during aspergillosis by mitigating release of neutrophil extracellular traps

Abstract

Invasive aspergillosis is characterized by lung hemorrhage and release of extracellular heme, which promotes fungal growth. Heme can also mediate tissue injury directly, and both fungal growth and lung injury may induce hemorrhage. To assimilate these interdependent processes, we hypothesized that, during aspergillosis, heme mediates direct lung injury independent of fungal growth, leading to worse infection outcomes, and the scavenger protein hemopexin mitigates these effects. Mice with neutropenic aspergillosis developed a time-dependent increase in lung extracellular heme and a corresponding hemopexin induction. Hemopexin deficiency resulted in markedly increased lung injury, fungal growth, and lung hemorrhage. Using a computational model of the interactions of Aspergillus, heme, and the host, we predicted a critical role for heme-mediated generation of neutrophil extracellular traps (NETs) in this infection. We tested this prediction using a fungal strain unable to grow at body temperature and found that extracellular heme and fungal exposure synergized to induce lung injury by promoting NET release, and disruption of NET was sufficient to attenuate lung injury and fungal burden. These data implicate heme-mediated NETosis in both lung injury and fungal growth during aspergillosis, resulting in a detrimental positive feedback cycle that can be interrupted by scavenging heme or disrupting NETs.

Authors

Ganlin Qu, Henrique A.L. Ribeiro, Angelica L. Solomon, Luis Sordo Vieira, Yana Goddard, Nickolas G. Diodati, Arantxa V. Lazarte, Matthew Wheeler, Reinhard Laubenbacher, Borna Mehrad

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Figure 1

Lung heme content and hemopexin during invasive pulmonary aspergillosis.

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Lung heme content and hemopexin during invasive pulmonary aspergillosis....
(A) Schematic representation of the experimental protocol. Image made in BioRender. (B) The concentration of heme in bronchoalveolar lavage (BAL) over the first 3 days of invasive aspergillosis. (C and D) Time series of liver hemopexin transcription and plasma and lung hemopexin protein concentrations. In panels B–D, values represent mean and standard error of the mean (SEM) of n = 8–11 animals per time point or per group in each panel, and time 0 indicates neutropenic but uninfected animals. (E and F) Correlation of liver hemopexin transcription and plasma hemopexin protein and of lung and plasma hemopexin concentration. The solid line represents the linear regression, and dashed lines represent the 95% confidence intervals. These panels show a reanalysis of the data in panels C and D. (G) Effect of exogenous administration of heme on plasma hemopexin during aspergillosis. Intrapulmonary administration of heme was performed on day 1 of infection, and plasma hemopexin was measured on day 2 of infection. Dots represent individual animals and horizontal lines represent medians. Each figure represents pooled data from 2 independent experiments. *, **, ***, and **** denote P values of <0.05, <0.01, <0.001, and <0.0001, respectively. Statistical tests: B–D, 1-way ANOVA; E and F, simple linear regression; G, Kruskal-Wallis 1-way ANOVA with Dunn’s multiple-comparison test.