Inflammation is a key part of the wound healing
process that regulates not only the rate of healing but also the degree of
scarring of the skin. Flightless I
(Flii) has been identified as a negative regulator of wound healing, and reducing
its activity either genetically or by using a neutralising antibody improves
the rate of healing with a concurrent increase in cell migration and
proliferation in mouse and pig incisional and excisional wounds. Flii has also been shown to interact with the
Toll-Like Receptor 4 (TLR4) activator lipopolysaccharide (LPS) as well as the
TLR signalling molecule MyD88. This
study therefore aimed to investigate the effects of Flii on the inflammatory
response during wound healing and whether any effects were via changes to TLR
signalling. Three mouse genotypes were
used with either: reduced levels of Flii (Flii+/-), normal levels of
Flii (WT) or increased levels of Flii (FliiTg/Tg). Increased Flii gene expression lead to altered
TLR4 activation and signalling through the MyD88 pathway with increased
expression of pro-inflammatory cytokines TNF-α and IL-6. This lead to an elevated inflammatory
response, with a prolonged presence of M1 macrophages within the wound,
resulting in delayed healing. Contrary
to this, mice with reduced levels of Flii(Flii+/-) showed an
increase in TLR4 signalling through elevated levels of IRF3 and M2 macrophages
within the wounds. This lead to a
reduction in the overall inflammatory response and an increase in the rate of
healing. These results show that Flii may
directly modulate TLR signalling and that manipulating the expression of Flii
in a wound may be a therapeutic strategy used to reduce inflammatory responses
and therefore lead to improved wound outcomes.