Flightless I Negatively Regulates Macrophage Surface TLR4, Delays Early Inflammation, and Impedes Wound Healing

Abstract

TLR4 plays a pivotal role in orchestrating inflammation and tissue repair. Its expression has finally been balanced to initiate the early, robust immune response necessary for efficient repair without excessively amplifying and prolonging inflammation, which impairs healing. Studies show Flightless I (Flii) is an immunomodulator that negatively regulates macrophage TLR4 signalling. Using macrophages from Flii+/−, WT, and FliiTg/Tg mice, we have shown that elevated Flii reduces early TLR4 surface expression, delaying and reducing subsequent TNF secretions. In contrast, reduced Flii increases surface TLR4, leading to an earlier robust TNF peak. In Flii+/− mice, TLR4 levels peak earlier during wound repair, and overall healing is accelerated. Fewer neutrophils, monocytes and macrophages are recruited to Flii+/− wounds, leading to fewer TNF-positive macrophages, alongside an early peak and a robust shift to M2 anti-inflammatory, reparative Ym1+ and IL-10+ macrophages. Importantly, in diabetic mice, high Flii levels are found in plasma and unwounded skin, with further increases observed in their wounds, which have impaired healing. Lowering Flii in diabetic mice results in an earlier shift to M2 macrophages and improved healing. Overall, this suggests Flii regulation of TLR4 reduces early inflammation and decreases the M2 macrophage phenotype, leading to impaired healing.

Skin barrier-inflammatory pathway is a driver of the psoriasis-atopic dermatitis transition

“…It has been shown that the use of neutralizing antibodies against Flii attenuates the inflammatory response induced by imiquimod in psoriasis mice ( 147 ). Regarding the fundamental role of the TLR4-NF-κB pathway in the pathogenesis of psoriasis ( 148 ), Flii may interfere with the binding of TLR4 to myeloid differentiation primary response protein 88 (MyD88), which thereby inhibits the NF-κB pathway ( 149 ). Resultantly, this leads to a reduction in the release of downstream inflammatory factors and a decrease in psoriasis symptoms.…”

FLI1 localization to the chlamydial inclusion involves multiple mechanisms

“…Both are reported to act as regulators of eukaryotic protein expression; FLI1 is a co-activator of nuclear receptor mediated transcription (e.g., estrogen receptor and glucocorticoid receptor) (30)(31)(32), while LRRF1 is a known transcriptional repressor with DNA binding activity (e.g., tnf) (33)(34)(35)(36). Both are also involved in regulating host innate immune responses to infection, though their activity has been shown to be both antagonistic and synergistic (37)(38)(39)(40)(41)(42)(43).…”