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Severe angiopathy is a major driver for diabetes associated secondary complications. Knowledge on underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors (SPs) at the edge of non-healing diabetic wounds in a murine db/db model, closely mirroring human type II diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ SPs. This compensates for the profoundly reduced angiogenin expression in non-treated murine chronic diabetic wounds. Silencing of angiogenin in ABCB5+ SPs prior to injection significantly reduced angiogenesis and delayed wound closure in diabetic db/db mice implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining SPs-based therapies of non-healing diabetic foot ulcers and other pathologies with impaired angiogenesis.

Mesenchymal stem cells (MSCs) have properties which make them promising for the treatment of chronic non-healing wounds. A major so far unmet challenge is the efficient, safe and painless delivery of MSCs to skin wounds. Recently, a surface carrier of medical-grade silicone coated by plasma polymerisation with a thin layer of acrylic acid (ppAAc) was developed, and shown to successfully deliver MSCs to deepithelialised human dermis in vitro. Here we studied the potential of the ppAAc carrier to deliver human adipose tissue derived MSCs (AT-MSCs) to murine full-thickness excisional skin wounds in vivo. Further we investigate the mechanism of action of MSCs in accelerating wound healing in these wounds. AT-MSCs cultured on ppAAc carriers for 4 days or longer fully retained their cell surface marker expression profile, colony-forming-, differentiation- and immunosuppressive potential. Importantly, AT-MSCs delivered to murine wounds by ppAAc carriers significantly accelerated wound healing, similar to AT-MSCs delivered by intradermal injection. More than 80% of AT-MSCs were transferred from carriers to wounds in 3 days. AT-MSCs were detectable in wounds for at least 5 days after wounding. Carrier delivered AT-MSCs were demonstrated to have the capacity to down-modulate TNF-α-dependent inflammation, increase anti-inflammatory M2 macrophage numbers, and induce TGF-β(1)-dependent angiogenesis, myofibroblast differentiation and granulation tissue formation, thereby enhancing overall tissue repair.

Psoriasis is a T-cell-mediated inflammatory disease. Previous studies focused on lymphocyte function-associated antigen 1 (LFA-1)-expressing T cells as a molecular target for therapeutic intervention. By contrast, information on therapeutic effects and the underlying mechanism of blocking the LFA-1 counter receptor, ICAM-1 is scarce. Here, we used the CD18 (beta2-integrin) hypomorphic (CD18hypo) mouse model of psoriasis to investigate the therapeutic role of extracellular adherence protein (Eap) of Staphylococcus aureus, which exerts antiinflammatory activities by interacting with the ICAM-1 function. We show that ICAM-1 is predominantly upregulated on endothelial cells in lesional skin of CD18hypo mice. In vitro Eap was found to disrupt cell-cell contacts between T cells and dendritic cells, and inhibit T-cell proliferation. By contrast, in vivo Eap rather blocked transmigration of T cells from vessels to inflamed skin of CD18hypo mice, but did not inhibit their proliferation and activation. Most importantly, Eap successfully suppressed the disease by blocking T-cell extravasation into the inflamed skin. Together, these data indicate that interaction between LFA-1 and ICAM-1 is causally involved in the pathogenesis of psoriasiform skin inflammation, and targeting ICAM-1 to selectively block T-cell extravasation by Eap without immune suppression may represent a potential therapeutic strategy for psoriasis.

Deregulation of reactive oxygen intermediates (ROI) resulting in either too high or too low concentrations are commonly recognized to be at least in part responsible for many changes associated with aging. This article reviews ROI-dependent mechanisms critically contributing to the decline of immune function during physiologic - or premature - aging. While ROI serve important effector functions in cellular metabolism, signalling and host defence, their fine-tuned generation declines over time, and ROI-mediated damage to several cellular components and/or signalling deviations become increasingly prevalent. Although distinct ROI-associated pathomechanisms contribute to immunosenescence of the innate and adaptive immune system, mutual amplification of dysfunctions may often result in hyporesponsiveness and immunodeficiency, or in chronic inflammation with hyperresponsiveness/deregulation, or both. In this context, we point out how imbalanced ROI contribute ambiguously to driving immunosenescence, chronic inflammation and autoimmunity. Although ROI may offer a distinct potential for therapeutic targeting along with the charming opportunity to rescue from deleterious processes of aging and chronic inflammatory diseases, such modifications, owing to the complexity of metabolic interactions, may carry a marked risk of unforeseen side effects.

Liver damage in humans is induced by various insults including alcohol abuse, hepatitis B/C virus infection, autoimmune or metabolic disorders and, when persistent, leads to development of liver fibrosis. Because the nuclear factor-jB (NF-jB) system is activated in response to several of these stresses, we hypothesized that NF-jB activation in hepatocytes may contribute to fibrosis development. To activate the NF-jB signaling pathway in a timeand celltype-specific manner in the liver, we crossed transgenic mice carrying the tetracycline-responsive transactivator under the control of the liver activator protein promotor with transgenic mice carrying a constitutively active form of the Ikbkb gene (IKK2 protein [CAIKK2]). Double-transgenic mice displayed doxycycline-regulated CAIKK2 expression in hepatocytes. Removal of doxycycline at birth led to activation of NF-jB signaling, moderate liver damage, recruitment of inflammatory cells, hepatocyte proliferation, and ultimately to spontaneous liver fibrosis development. Microarray analysis revealed prominent up-regulation of chemokines and chemokine receptors and this induction was rapidly reversed after switching off the CAIKK2 expression. Turning off the transgene expression for 3 weeks reversed stellate cell activation but did not diminish liver fibrosis. The elimination of macrophages by clodronate-liposomes attenuated NF-jB-induced liver fibrosis in a liver-injury-independent manner. Conclusion: Our results revealed that hepatic activation of IKK/NF-jB is sufficient to induce liver fibrosis by way of macrophage-mediated chronic inflammation. Therefore, agents controlling the hepatic NF-jB system represent attractive therapeutic tools to prevent fibrosis development in multiple chronic liver diseases. (HEPATOLOGY 2012;56:1117-1128)