Similarly , our in vitro anti - inflammatory bioassay data was corroborated by in vivo improvement in inflammatory milieu observed in FPF - treated ischemic wounds ( Figures 6 and 7 ) . The incessant and elevated presence in proinflammatory cytokines CINC-1 , CINC-2 , CINC-3 , LIX , and IL-6 , being crucial neutrophil traffickers , cause exacerbated levels of neutrophil incidence , resulting in further tissue damage [ 27,[41][42][43 ] . Unlike FPF - treated wounds , control animals exhibited a significant increase in neutrophil chemoattractants that correlated with the upsurge in neutrophils to the wound bed ( Figure 6B ) . Downregulation of genes , including Ccl12 , Cxcl1 , Cxcl3 , IL-1β , IL-6 , Ptgs2 , and TNF , that contribute to inflammatory responses were observed in FPF - treated animals [ 44][45][46][47 ] . Furthermore , adhesion molecules L - selectin and JAM - A that are critical in neutrophil migration and activation were reduced upon FPF treatment . Both L - selectin and JAM - A heavily influence neutrophil extravasation and infiltration into the ischemic tissue environment [ 48][49][50 ] . Levels of eotaxin , which induces recruitment of not only eosinophils , but also basophils , neutrophils , and macrophages , were significantly reduced in FPF - treated animals [ 51 ] . We also saw significantly lower levels of MIP-1α , RANTES , TREM-1 , and activin A , which are critical macrophage chemoattractants in wound repair [ 52][53][54][55 ] . TWEAK signaling further modulates inflammatory responses and enhances the production of proinflammatory cytokines , including RANTES [ 56 ] . While the expression of RANTES and its functional response to MIP-1α are enhanced during differentiation of monocytes to macrophages , activin A alters macrophage polarization by promoting a proinflammatory M1 phenotype and inhibiting the acquisition of anti - inflammatory M2 macrophage markers [ 55,57 ] . Although we did not find significant differences in the total number of macrophages , we detected a substantially higher number of M2 macrophages in FPF - treated animals ( Figure 6C ) . Concurrently , we also found that FPF treatment led to an increase in fractalkine / CX3CL1 , which induces VEGF - mediated angiogenesis potential in CX3CR1 - expressing M2 macrophages [ 58 ] .