Fig. 2: Regulatory processes activated in macrophages upon UPEC infection.

Some of the key events initiated in macrophages upon UPEC infection and/or phagocytosis are shown. ATG16L1 is recruited to internalized UPEC, with bacteria being engulfed into autophagosomes via autophagy. TLR4 homodimers recognize UPEC and trigger pro-inflammatory signaling, including NF-κB activation. TLR signaling upregulates inflammasome components, with α-hemolysin-positive UPEC strains triggering inflammasome activation and caspase-1-dependent processing of pro-IL-1β. This enables secretion of mature IL-1β via membrane pores. TLR signaling also turns on the zinc toxicity response in macrophages, likely via regulated expression of both SLC30A zinc exporters and SLC39A zinc importers, with UPEC strains that survive in macrophages effectively evading this antimicrobial pathway. NF-κB activation increases the production of the pro-inflammatory cytokine IL-6, which modulates intracellular iron levels by increasing the production of the ferritin-iron intracellular complex and regulating levels of LCN-2 and ferroportin. Ferritin and iron form an intracellular complex, and LCN-2 maintains optimal iron levels in the cell by exporting excess iron out. An intrinsic clock controls the capacity of macrophages to sense and respond to UPEC, with circadian control of IL-6 production likely to be particularly important in macrophage/UPEC interactions and host defense.