Infusion of Phagocytic Macrophages Overexpressing CPT1a Ameliorates Kidney Fibrosis in the UUO Model.

Priscila Calle,Georgina Hotter,Paula Mera,Anna Sola,Dolors Serra,Miriam García,Soraya Játiva,Laura Herrero,Selene Torrico,Angeles Muñoz

doi:10.3390/cells10071650

Abstract

Phagocytosis is an inherent function of tissue macrophages for the removal of apoptotic cells and cellular debris during acute and chronic injury; however, the dynamics of this event during fibrosis development is unknown. We aim to prove that during the development of kidney fibrosis in the unilateral ureteral obstruction (UUO) model, there are some populations of macrophage with a reduced ability to phagocytose, and whether the infusion of a population of phagocytic macrophages could reduce fibrosis in the murine model UUO. For this purpose, we have identified the macrophage populations during the development of fibrosis and have characterized their phagocytic ability and their expression of CPT1a. Furthermore, we have evaluated the therapeutic effect of macrophages overexpressing CPT1a with high phagocytic skills. We evidenced that the macrophage population which exhibits high phagocytic ability (F4/80low-CD11b) in fibrotic animals decreases during the progression of fibrosis while the macrophage population with lower phagocytic ability (F4/80high-CD11b) in fibrotic conditions, conversely, increases and CPT1a macrophage cell therapy with a strengthening phagocytic ability is associated with a therapeutic effect on kidney fibrosis. We have developed a therapeutic approach to reduce fibrosis in the UUO model by enrichment of the kidney resident macrophage population with a higher proportion of exogenous phagocytic macrophages overexpressing CPT1a.

Highlights

Kidney fibrosis is a second-line healing program that only occurs if normal kidney repair is impaired or consistently suppressed by ongoing tissue injury and inflammation [1]
Our results revealed that macrophage phagocytosis and inflammatory phenotype are dependent on intracellular lipid accumulation and CPT1a expression
Levels of mRNA fibrosis-related genes, such as col1a1 and fibronectin, during ureteral obstruction (UUO) at different time points reveal that the main expression peak occurred at day 5 after UUO (Figure 1d), indicating that the principal modification occurred during the transition between day 3 and 5 after the obstruction

Summary

Introduction

Kidney fibrosis is a second-line healing program that only occurs if normal kidney repair is impaired or consistently suppressed by ongoing tissue injury and inflammation [1]. After kidney injury, the innate immune system is activated and orchestrates the recruitment of inflammatory cells from the circulation. Resident immune cells, including macrophages, produce chemoattractant that enhance inflammatory responses by recruiting more leukocytes. During tissue injury, changing tissue environments shape the macrophages phenotype towards the anti-inflammatory to provide them with additional functional properties that meet the tissue’s need to address the danger. At the later stage after injury, macrophages contribute to the removal of fibrous tissue, mediating the resolution phase of healing that includes collagen remodeling. Little is known about how a particular population of macrophages terminates the repair response and becomes pro or anti fibrotic [2]. The knowledge of the agent modulating the phenotype of these macrophages or ex-vivo production of such cells possesses great therapeutic potential

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