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

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 STAT1dependent 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.

Acute Hemolysis and Heme Suppress Anti-CD40 Antibody-Induced Necro-Inflammatory Liver Disease

“…Our group has shown that mice with spherocytosis and chronic hemolysis were resistant to anti-CD40-induced necro-inflammatory liver disease and nonalcoholic steatohepatitis (NASH) (22). In addition, Olonisakin et al reported that acute hemolysis induced by the transfusion of stressed erythrocytes impaired the innate immune response to Klebsiella pneumoniae infection, aggravating sepsis, and mortality of infected mice (23). Both studies defined an antiinflammatory and immunosuppressive heme-signaling pathway that includes heme-activation of Nfe2l2/Nrf2 with significant suppression of Stat1 and interferon-regulated genes.…”

“…Growing evidence indicates that heme accumulation in macrophages that results from erythrophagocytosis or heme clearance is a suppressor of inflammation and innate immunity (21)(22)(23)(24)(25). In chronic genetic hemolytic anemia, erythrophagocytosis profoundly modified the landscape of liver macrophages, skewing their transformation into anti-inflammatory erythrophagocytes that attenuated immune-mediated acute and chronic pathologies in the liver (22).…”

“…In chronic genetic hemolytic anemia, erythrophagocytosis profoundly modified the landscape of liver macrophages, skewing their transformation into anti-inflammatory erythrophagocytes that attenuated immune-mediated acute and chronic pathologies in the liver ( 22 ). Intracellular heme signaling may also compromise host defense to bacterial infections and adversely affect survival in sepsis ( 23 , 26 ).…”

Finding Order in the Chaos: Outstanding Questions in Klebsiella pneumoniae Pathogenesis

“…Following infection in the lung, macrophages also function to limit extrapulmonary proliferation at tissue sites such as the liver and spleen. It was recently shown that severe KPPR1 infection heightens erythrophagocytosis by macrophages (a conserved innate immune response triggered by Toll-like receptor stimulation) and leads to suppression of interferon signaling through heme-mediated STAT1 dysregulation ( 96 ). As a consequence, macrophages were observed to acquire an immunosuppressive phenotype, which leads to an impaired ability of mice to control K. pneumoniae replication, exaggerated systemic inflammatory responses, and increased host mortality ( 96 ).…”

“…It was recently shown that severe KPPR1 infection heightens erythrophagocytosis by macrophages (a conserved innate immune response triggered by Toll-like receptor stimulation) and leads to suppression of interferon signaling through heme-mediated STAT1 dysregulation ( 96 ). As a consequence, macrophages were observed to acquire an immunosuppressive phenotype, which leads to an impaired ability of mice to control K. pneumoniae replication, exaggerated systemic inflammatory responses, and increased host mortality ( 96 ). This study highlights the importance of macrophages in controlling K. pneumoniae replication, and in regulating the inflammatory response at different tissue sites.…”