Trauma-induced heme release increases susceptibility to bacterial infection
Ghee Rye Lee, … , Carl J. Hauser, Leo E. Otterbein
Ghee Rye Lee, … , Carl J. Hauser, Leo E. Otterbein
Published September 14, 2021
Citation Information: JCI Insight. 2021;6(20):e150813. https://doi.org/10.1172/jci.insight.150813.
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Research Article Infectious disease Inflammation

Trauma-induced heme release increases susceptibility to bacterial infection

Abstract

Infection is a common complication of major trauma that causes significantly increased morbidity and mortality. The mechanisms, however, linking tissue injury to increased susceptibility to infection remain poorly understood. To study this relationship, we present a potentially novel murine model in which a major liver crush injury is followed by bacterial inoculation into the lung. We find that such tissue trauma both impaired bacterial clearance and was associated with significant elevations in plasma heme levels. While neutrophil (PMN) recruitment to the lung in response to Staphylococcus aureus was unchanged after trauma, PMN cleared bacteria poorly. Moreover, PMN show > 50% less expression of TLR2, which is responsible, in part, for bacterial recognition. Administration of heme effectively substituted for trauma. Finally, day 1 trauma patients (n = 9) showed similar elevations in free heme compared with that seen after murine liver injury, and circulating PMN showed similar TLR2 reduction compared with volunteers (n = 6). These findings correlate to high infection rates.

Authors

Ghee Rye Lee, David Gallo, Rodrigo W. Alves de Souza, Shilpa Tiwari-Heckler, Eva Csizmadia, James D. Harbison, Sidharth Shankar, Valerie Banner-Goodspeed, Michael B. Yaffe, Maria Serena Longhi, Carl J. Hauser, Leo E. Otterbein

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Figure 5

Heme decreases bacterial clearance in the lung and decreases TLR2 expression in PMN in vivo.

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Heme decreases bacterial clearance in the lung and decreases TLR2 expres...
(A and B) Fold change of TLR2 MFI in PMN in the blood and the BM, 4 hours after heme challenge alone (50 mg/kg, i.p.) in vivo (n = 6/group). (C) Fold change of S. aureus CFU in BALF 24 hours after infection with and without heme challenge. Mice were challenged with heme 4 hours before the infection (50 mg/kg, i.p.; n = 10–12/group). (D) Fold change of TLR2 MFI in PMN in BAL 24 hours after infection with and without heme challenge (n = 4/group). (E) A representative flow cytometry analysis image showing the MFI of TLR2 in PMN in the BAL. Blue represents PMN in BAL from control mice, and red represents PMN from mice with heme challenge. Gray represents unstained cells. (F and G) Fold change of TLR2 MFI in PMN in the blood and the BM 24 hours after infection, with and without heme challenge (n = 4/group). (H–J) Levels of KC, IP-10, and MIP-1α in the BALF at the baseline (n = 3), 24 hours after lung infection with and without heme challenge (n = 4/group). (K) Fold change of reactive oxygen species (ROS) release in PMN treated with naive or trauma serum in response to S. aureus exposure in vitro (3 independent experiments, each with n = 3–4/group). ROS release is measured by the AUC. All data are presented as mean ± SEM. Statistical analyses for H, I, and J were performed by 1-way ANOVA with post hoc Tukey’s test. All other P values were calculated by unpaired 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.