Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout (Mll1 f/f Lyz2 Cre+ ), we determined that MLL1 drives Tlr4 expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the Tlr4 promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either Tlr4 (Tlr4 2/2 ) or myeloid-specific Tlr4 (Tlr4 f/f Lyz2 Cre+ ) resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.

Filamentous actinobacteria like Streptomyces undergo two distinct modes of cell division, leading to the partitioning of growing hyphae into multicellular compartments via cross-walls and to the septation and release of unicellular spores. While some progress has been made towards the regulation of sporulation-specific cell division, specific determinants for cross-wall formation and the importance of hyphal compartmentalization for Streptomyces development have remained unknown. Here we describe SepX, an actinobacterial-specific protein that is crucial for both cell division events in Streptomyces. We show that sepX-deficient mutants grow without cross-walls and that this substantially impairs the fitness of colonies and the coordinated progression through the developmental life cycle. Protein interaction studies and live-cell imaging suggest that SepX functions to spatially stabilize the divisome, a mechanism that also requires the dynamin-like protein DynB. Collectively, this work identifies an important determinant for cell division in filamentous actinobacteria that is required for multicellular development and sporulation.