The process of inflammation is orchestrated by macrophages, according to their state of differentiation:
thus, classically activated (M1) macrophages initiate the process by elaborating proinflammatory cytokines and
reactive oxygen species, whereas the latter phase is controlled by alternatively activated macrophages (M2) to
resolve inflammation and promote tissue remodelling with the release of growth factors. In a simple human inflammatory
response, such as acute crystal arthropathy, macrophages progress linearly through M1 and M2
phases; however, in chronic inflammatory responses, such as atherosclerosis and Diabetic Nephropathy (DN),
both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis.
A key macrophage receptor that regulates conversion from M1 to M2 is CD163, the hemoglobin scavenger receptor.
Scavenging of hemoglobin:haptoglobin (Hb:Hp) complexes via CD163 leads to nuclear translocation of the
transcription factor Nrf2 (NF-E2-related factor 2), upregulation of heme oxygenase (HO)-1 cytoprotective protein,
and release of interleukin (IL)-10 anti-inflammatory cytokine; IL-10 is then linked in a positive feedback
loop to further CD163 expression. The potency of this M1/M2 switching pathway is underscored by the fact that
human Hp2 polymorphisms are associated with worsened clinical outcomes for diabetic complications, including
DN. Parallel observations in animals show that HO-1 activation by hemin protects against DN in rodent models
This review discusses the concept that Nrf2/HO-1 acts as a ‘therapeutic funnel’ through which a range of natural
and synthetic anti-oxidants may drive M1 to M2 switching and improved kidney function in diabetes. We also
discuss our observations on the evolution of M1/M2 phenotypes in a human model of wound healing which has
presented intriguing potential drug targets for DN, such as eotaxin/CCR3.