Nrf2 driven macrophage responses in diverse pathophysiological contexts: Disparate pieces from a shared molecular...

The wide anatomical distribution of macrophages and their vast array of functions match various polarization states and their involvement in homeostasis and disease. The confluence of different cellular signaling networks, including direct involvement in inflammation, at the doorstep of the transcription factor Nuclear Factor- erythroid (NF-E2) p45-related factor 2 (Nrf2) activation raises the importance of deciphering the molecular circuitry at the background of multiple-discrete and antagonistic yet flexible and contextual pathways. While we primarily focus on wound healing and repair mechanisms that are affected in diabetic foot ulcers (DFUs), we strive to explore the striking similarities and differences in molecular events including inflammation, angiogenesis, and fibrosis during tissue injury and wound persistence that accumulates pro-inflammatory senescent macrophages, as a means to identify possible targets or cellular mediators to lessen DFU disease burden. In addition, the role of iron in the modulation of Nrf2 response in macrophages is crucial and reviewed here. Targeted approaches, unlike conventional treatments, in DFU management will require the review and re-assessment of mediators with relevance to other pathological conditions.