Stressed erythrophagocytosis induces immunosuppression during sepsis through heme-mediated STAT1 dysregulation

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Abstract

Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent red blood cells (sRBC). Macrophages are also essential in defense against microbial threats, but pathologic states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype following intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, as K. pneumoniae mutant lacking siderophore function recapitulated findings observed with wildtype strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and interferon-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulates the STAT1 pathway with implications in severe infection.

Authors

Tolani F. Olonisakin, Tomeka L. Suber, Shekina Gonzalez-Ferrer, Zeyu Xiong, Hernán F. Peñaloza, Rick van der Geest, Yuting Xiong, David O. Osei-Hwedieh, Jesus Tejero, Matthew R. Rosengart, Wendy M. Mars, Daria Van Tyne, Andreas Perlegas, Samuel Brashears, Daniel B. Kim-Shapiro, Mark T. Gladwin, Michael A. Bachman, Eldad A. Hod, Claudette St. Croix, Yulia Y. Tyurina, Valerian E. Kagan, Rama K. Mallampalli, Anuradha Ray, Prabir Ray, Janet S. Lee