Macrophages
are central to the pathogenesis of kidney
disease and
serve as an effective therapeutic target for kidney injury and fibrosis.
Among them, M2-type macrophages have double-edged effects regarding
anti-inflammatory effects and tissue repair. Depending on the polarization
of the M2 subtypes (M2a or M2c) in the diseased microenvironment,
they can either mediate normal tissue repair or drive tissue fibrosis.
In renal fibrosis, M2a promotes disease progression through macrophage-to-myofibroblast
transition (MMT) cells, while M2c possesses potent anti-inflammatory
functions and promotes tissue repair, and is inhibited. The mechanisms
underlying this differentiation are complex and are currently not
well understood. Therefore, in this study, we first confirmed that
M2a-derived MMT cells are responsible for the development of renal
fibrosis and demonstrated that the intensity of TGF-β signaling
is a major factor determining the differential polarization of M2a
and M2c. Under excessive TGF-β stimulation, M2a undergoes a
process known as MMT cells, whereas moderate TGF-β stimulation
favors the polarization of M2c phenotype macrophages. Based on these
findings, we employed targeted nanotechnology to codeliver endoplasmic
reticulum stress (ERS) inhibitor (Ceapin 7, Cea or C) and conventional
glucocorticoids (Dexamethasone, Dex or D), precisely modulating the
ATF6/TGF-β/Smad3 signaling axis within macrophages. This approach
calibrated the level of TGF-β stimulation on macrophages, promoting
their polarization toward the M2c phenotype and suppressing excessive
MMT polarization. The study indicates that the combination of ERS
inhibitor and a first-line anti-inflammatory drug holds promise as
an effective therapeutic approach for renal fibrosis resolution.