An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

Abstract

Uncontrolled macrophage activation is now considered to be a critical event in the pathogenesis of chronic inflammatory diseases such as atherosclerosis, multiple sclerosis, and chronic venous leg ulcers. However, it is still unclear which environmental cues induce persistent activation of macrophages in vivo and how macrophage-derived effector molecules maintain chronic inflammation and affect resident fibroblasts essential for tissue homeostasis and repair. We used a complementary approach studying human subjects with chronic venous leg ulcers, a model disease for macrophage-driven chronic inflammation, while establishing a mouse model closely reflecting its pathogenesis. Here, we have shown that iron overloading of macrophages -as was found to occur in human chronic venous leg ulcers and the mouse model -induced a macrophage population in situ with an unrestrained proinflammatory M1 activation state. Via enhanced TNF-α and hydroxyl radical release, this macrophage population perpetuated inflammation and induced a p16 INK4a -dependent senescence program in resident fibroblasts, eventually leading to impaired wound healing. This study provides insight into the role of what we believe to be a previously undescribed iron-induced macrophage population in vivo. Targeting this population may hold promise for the development of novel therapies for chronic inflammatory diseases such as chronic venous leg ulcers.

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

“…A similar M1 polarization, which is associated with a chronic proinflammatory state, has also been reported in chronic venous ulcers. 30 SP treatment at day 10 reduced the M1/M2 ratio in the WT diabetic mice and had a similar effect on MCP-1 skin expression, which is implicated in macrophage recruitment in adipose tissue. 18,31 A possible mechanism of action of SP is by reducing oxidative stress.…”

Valence State Manipulation of Cerium Oxide Nanoparticles on a Titanium Surface for Modulating Cell Fate and Bone Formation

“…This early inflammatory response is highly beneficial to the host, it must subsequently be terminated to avoid tissue damage and to promote tissue regeneration 14. Any unrestrained pro‐inflammatory M1 macrophage polarization induced by biomaterials will therefore impair new bone formation and osseointegration[[qv: 8b]] and prevent wound healing 47. Therefore, CeONPs biomaterials must have appropriate modulatory effects on the balance between antiinflammation and pro‐inflammation immune reactions in order to elicit the desired outcomes of bone regeneration and osseointegration.…”

Macrophages – sensors and effectors coordinating skin damage and repair

“…Adult mouse [16] Macrophages play critical roles in skeletal muscle regeneration Adult mouse [50,58] Macrophages exert specific roles at diverse stages of repair and orchestrate the natural sequence of repair phases in skin Adult mouse [4,[17][18][19] Gr-1 + CD11b + cells contribute to injury-induced neo-vascularization Adult mouse [42] Non-inflammatory Ly6C low MHCII high wound macrophages promote wound healing Adult mouse [43] Persisting pro-inflammatory macrophages impair wound healing in venous Ulcers Human [40] classical/alternative macrophage activation is operative at the cutaneous wound site and which of the micro-environmental cues may direct macrophage activation. Furthermore, the functional relation between the recruitment of diverse blood monocyte subtypes into damaged tissue and their potential activation to the alternative or classical macrophage phenotype was unclear.…”

“…Impaired healing conditions, such as vascular diseases, diabetes mellitus, auto-inflammatory disorders and/or aging are frequently associated with persistent tissue-destructive inflammation [3,[40][41][42]. The observation that during effective healing progression macrophages switch their activation phenotype towards M2 polarization indicates that this switch may be disturbed in pathological healing conditions [40][41][42][43].…”

“…The observation that during effective healing progression macrophages switch their activation phenotype towards M2 polarization indicates that this switch may be disturbed in pathological healing conditions [40][41][42][43]. In fact, studies in patients with chronic venous leg ulcers suggest that the prolonged accumulation and persistence of M1 macrophages may be harmful and tissue-destructive contributing to pathological healing conditions [40].…”