Precisely Regulating M2 Subtype Macrophages for Renal Fibrosis Resolution

Abstract

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 TGFβ 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.

Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease

“…Excessive TGF-β stimulation induces M2a macrophages to undergo MMT, while moderate TGF-β stimulation promotes the polarization of M2c macrophages. By regulating the activating transcription factor 6 (ATF6)/TGF-β/Smad3 signaling axis in macrophages and adjusting TGF-β levels, it is possible to guide their polarization towards the M2c phenotype and inhibit excessive MMT polarization [169]. However, another study suggests that polarized M2c macrophages promote the epithelial-to-mesenchymal transition of human renal tubular epithelial cells [170].…”

“…Another research investigation employed specialized nanotechnology to simultaneously deliver an endoplasmic reticulum stress (ERS) inhibitor (Ceapin 7) and dexamethasone, successfully regulating the ATF6/TGFβ/Smad3 signaling pathway in macrophages. This approach controlled the extent of TGF-β activation in macrophages, facilitating their differentiation towards the M2c phenotype while inhibiting excessive MMT polarization [169].…”

Renal macrophages and NLRP3 inflammasomes in kidney diseases and therapeutics

“…In contrast to its traditionally activated counterpart, the M2 macrophage plays a role in resolving inflammation by possessing robust endocytic clearance abilities and generating trophic factors. This results in a decreased secretion of proinflammatory cytokines [ 44 , 45 ]. Specifically, M2 macrophages release trophic factors that stimulate angiogenesis and facilitate the healing of wounds by modifying the extracellular matrix (ECM) [ 46 ].…”

“…Different stimuli drive macrophage polarization into M2 phenotypes: M2a macrophage differentiation induced by IL-4 and IL-13 cytokines [ 35 , 50 ], TLR and/or IL-1R ligands and immune complexes induce M2b macrophage differentiation [ 51 , 52 ] conversely IL-10, TGF-β, and glucocorticoids leads to activate M2c macrophage differentiation [ 53 ]. The various sub-types of M2 macrophages exhibit both unique and overlapping roles [ 44 ]. M2a macrophages, for instance, stimulate TH2-like anti-inflammatory immune response, fostering both healing of wound and tissue fibrosis.…”

“…Macrophages sub-type M2b engage regulation of the immune system and play a role in TH2-like activation. On the other hand, M2c sub-type macrophages are involved in immunosuppression, participate in the remodeling of the matrix, and aid in tissue repair [ 44 , 54 – 57 ] Fig. 1 .…”