Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis

Abstract

Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyperyersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur-infected intestine revealed up-regulation in cytokine–cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1β signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light-chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.

Iron Metabolism and Immune Regulation

“…However, direct evidence regarding iron regulating neutrophils recruitment and inflammation is scarce. Published studies showed that interactions between iron and neutrophils is a pathological consequence of different types of disease ( 34 , 36 – 38 ). To the best our knowledge, the mechanism of iron regulating neutrophils recruitment and inflammation is most likely the chemokines secreted by certain types of cells influenced by iron, which means that the whole process is regulated by iron indirectly ( 34 , 36 – 38 ).…”

“…Published studies showed that interactions between iron and neutrophils is a pathological consequence of different types of disease ( 34 , 36 – 38 ). To the best our knowledge, the mechanism of iron regulating neutrophils recruitment and inflammation is most likely the chemokines secreted by certain types of cells influenced by iron, which means that the whole process is regulated by iron indirectly ( 34 , 36 – 38 ). In necrotizing fasciitis, keratinocyte-secreted hepcidin promotes CXCL1 production, thus promoting neutrophils recruitment.…”

“…Mechanistically, hepcidin induced FPN internalization and degradation, resulting in an increase in intracellular iron, which upregulates expression of CXCL1 in keratinocyte and subsequently promotes neutrophils recruitment ( 34 ). In some iron-overload disease, iron promotes neutrophils recruitment and inflammation by upregulating IL-1β ( 36 ). In Shiga-toxin-induced hemolytic–uremic syndrome, heme-scavenging proteins, haptoglobin, attenuated kidney platelet deposition and neutrophil recruitment, revealing the potential correlation between iron and neutrophil recruitment ( 37 ).…”

Postmortem grass carp (Ctenopharyngodon idella) muscle towards the disruption of integrity: a likely cause of abnormal regulation of tight junction and decreased antioxidant capacity

“…It was reported that the gene expressions of IFN‐γ increased in postmortem fish muscle (Tie et al ., 2022b), supporting our hypothesis. Study showed that the inhibition of myosin light chain kinase (MLCK) phosphorylation could attenuate the disruption of structural integrity (Cao et al ., 2013), while the increased expression of MLCK could disrupt the tight junctions by regulating the TJ proteins (Das et al ., 2022). The present research showed the increased gene expressions of MLCK, indicating that postmortem fish muscle was involved with the increased disruption of integrity.…”

Photodynamic Therapy Combined with Ferroptosis Is a Synergistic Antitumor Therapy Strategy

“…Iron ions play an important role in immunity and can regulate the functional transformation of macrophages, neutrophils, NK cells, T cells, and B cells. The specific performance is to promote the conversion of macrophages to M1 type; promote the recruitment of neutrophils; maintain the function of NK cells; promote the differentiation of T cells; and promote the proliferation of B cells [143][144][145][146][147]. Therefore, the immune response can explain the synergistic effect between ferroptosis and PDT, which is a promising antitumor strategy.…”