Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages.
To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importance. The insulin-resistant type II diabetic phenotype is functionally connected to obesity in rodent models of metabolic syndrome through the release of inflammatory mediators from adipose tissue. Here, we used the impaired wound-healing process in obese/obese (ob/ob) mice to investigate the impact of obesity-mediated systemic inflammation on cutaneous wound-healing processes. Systemic administration of neutralizing monoclonal antibodies against tumor necrosis factor (TNF)alpha (V1q) or monocyte/macrophage-expressed EGF-like module-containing mucin-like hormone receptor-like (Emr)-1 (F4/80) into wounded ob/ob mice at the end of acute wound inflammation initiated a rapid and complete neo-epidermal coverage of impaired wound tissue in the presence of a persisting diabetic phenotype. Wound closure in antibody-treated mice was paralleled by a marked attenuation of wound inflammation. Remarkably, anti-TNFalpha- and anti-F4/80-treated mice exhibited a strong reduction in circulating monocytic cells and reduced numbers of viable macrophages at the wound site. Our data provide strong evidence that anti-TNFalpha therapy, widely used in chronic inflammatory diseases in humans, might also exert effects by targeting "activated" TNFalpha-expressing macrophage subsets, and that inactivation or depletion of misbehaving macrophages from impaired wounds might be a novel therapeutic clue to improve healing of skin ulcers.
Goren
Itamar
I
Pharmazentrum frankfurt, ZAFES, Institut für Allgemeine Pharmakologie und Toxikologie, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
Müller
Elke
E
Schiefelbein
Dana
D
Christen
Urs
U
Pfeilschifter
Josef
J
Mühl
Heiko
H
Frank
Stefan
S
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D048909:Diabetes Complications / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D009000:Monocytes / Q000378:metabolism; D010641:Phenotype; D012867:Skin / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014945:Wound Healing
D014409:Tumor Necrosis Factor-alpha