Tissue repair and fibrosis are controlled by the interaction of different cell lineages, their
soluble factors and matrix signals. Recently, macrophages have been found to be crucial
for proper tissue repair. In particular, the role of Transforming growth factor-β1 (TGF-β1)
has been extensively studied during tissue repair and fibrosis. Fibrosis is characterized by
excessive production and deposition of extracellular matrix, as well as immune cell
infiltration. Macrophages are one of the main sources of TGF-β1. So far, studies on the
mechanisms of tissue repair and fibrosis have mainly focused on macrophages or TGF-β1
individually. However, the specific function of TGF-β1 on macrophages in tissue repair
and fibrosis still needs to be elucidated.
To understand the macrophage specific role of TGFβ1-TGFβRII signaling in tissue repair
and fibrosis, we generated a mouse model, which lacks TGFβRII in myeloid cells
(TGFβRIIfl/fl/LysMCre). We observed that during mechanical tissue injury TGFβRII
signaling in macrophages contributes to wound contraction, possibly by cross—talk
between macrophages and fibroblasts. The attenuated wound contraction was
accompanied by impaired myofibroblast differentiation and collagen deposition. However,
the loss of TGFβRII signaling in macrophages did not lead to reduced expression of TGF-
β1, which we proposed as one of the primary mechanisms in wound tissue underlying
reduced myofibroblast formation observed in TGFβRIIfl/fl/LysMCre mice.
Generation of cutaneous fibrosis by bleomycin injection for two and four weeks resulted in
reduced fibrosis in TGFβRIIfl/fl/LysMCre mice, compared to control mice. The mechanisms
leading to this phenotype were associated with reduced infiltration of immune cells,
reduced deposition of collagen and diminished production of inflammatory mediators such
as IL-1β, TNF-α and osteopontin-1 at the early stage of fibrosis formation. At the later
stage, the expression of inflammatory mediators in TGFβRIIfl/fl/LysMCre mice was not
altered compared to control mice, possibly due to compensatory mechanisms. Our data
leads to the hypothesis that the reduced fibrosis is caused by the reduced expression of
inflammatory mediators and accumulation of immune cells at the early stage of fibrosis in
TGFβRIIfl/fl/LysMCre mice.
Our results provide new insights into the crucial role of macrophage specific TGFβRII
signaling in tissue repair and fibrosis