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Thymosin Alpha 1 Enhances Macrophage Homing And Neutrophil Extracellular Trap Formation In Chronic Diabetic Wound
Shawn Jeffrey Loder, MD, Wayne Vincent Nerone, BS, Fuat Baris Bengur, MD, Phoebe Lee, BS, David Guerrero, BS, Lauren Kokai, PhD.
University of Pittsburgh, Pittsburgh, PA, USA.

PURPOSE: Biofilm formation is a major impediment to chronic wound resolution. Activation of innate immune sentinel cells such as macrophages and dendritic cells through microbe recognition by toll-like receptors (TLRs) is critical in the control and clearance of biofilms. Thymosin alpha-1 is an activator of the innate immune response and is one of the bioactive components of Thymosin Fraction V utilized in immune-replacement therapy. A primary function of Thymosin alpha-1 is TLR stimulation. The TLRs canonically activated by Thymosin alpha1 (TLR2/4/9) regulate biofilms in part via activation of the neutrophil extracellular trap (NET)-forming response (NETosis). Here we sought to determine if Thymosin alpha-1 reduces biofilm formation and improves closure in a murine model of infected diabetic wounds.
METHODS: Biofilm formation is a major impediment to chronic wound resolution. Activation of innate immune sentinel cells such as macrophages and dendritic cells through microbe recognition by toll-like receptors (TLRs) is critical in the control and clearance of biofilms. Thymosin alpha-1 is an activator of the innate immune response and is one of the bioactive components of Thymosin Fraction V utilized in immune-replacement therapy. A primary function of Thymosin alpha-1 is TLR stimulation. The TLRs canonically activated by Thymosin alpha1 (TLR2/4/9) regulate biofilms in part via activation of the neutrophil extracellular trap (NET)-forming response (NETosis). Here we sought to determine if Thymosin alpha-11 reduces biofilm formation and improves closure in a murine model of infected diabetic wounds.
RESULTS: No clinical signs or symptoms of invasive disease were noted during biofilm adherence. Animals pre-treated with Thymosin alpha-1 had a 46.6% decrease in biofilm adherence at 72-hours. At time of evaluation, no further evidence of healing was noted in infected wounds from vehicle-treated mice (107.98+/-13.30 % pre-treatment). In Thymosin alpha-1 treated groups, infected wound area significantly decreased by 69.63% +/- 8.69% (p=0.013 vs. vehicle-control). Granulation tissue from chronic wounds demonstrated significantly increased macrophage enrichment for CD11b(low; 1.11+/-0.07 % [vehicle control] vs 2.99+/-0.12 % [Thymosin alpha-1]; p<0.05); (mid; 0.71+/-0.03 % [vehicle control] vs 2.05+/-0.09 % [Thymosin alpha-1]; p<0.05); and (hi; 0.35+/-0.03 % [vehicle control] vs 0.91+/-0.04 % [Thymosin alpha-1]; p<0.05) populations. Peripheral blood neutrophils isolated from Thymosin alpha-1 demonstrated rapid and robust NETosis response to LPS-stimulation when compared with cells collected from vehicle-treated control.
CONCLUSION: Thymosin alpha-1 pre-treatment for 1-week significantly enhanced diabetic wound resilience against biofilm adherence. This occurred simultaneous with an increased enrichment of activated wound-resident macrophages in Thymosin alpha-1 treated groups. Blood collected from Thymosin alpha-1 pretreated mice was further sensitized to NET-formation in vitro.


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