Abstract
Tissue macrophages are important components of tissue homeostasis and inflammatory pathologies. In the peritoneal cavity, resident macrophages interact with a variety of immune cells and can exhibit broad range of phenotypes and functions. Forkhead-box-P3 (FOXP3)+ regulatory T cells (Tregs) play an indispensable role in maintaining immunological tolerance, yet whether, and how the pathological condition that results from the lack of functional Tregs affects peritoneal macrophages (PM) is largely unknown. We used FOXP3-deficient scurfy (Sf) mice to investigate PM behavior in terms of the missing crosstalk with Tregs. Here, we report that Treg deficiency induced a marked increase in PM numbers, which was reversed after adoptive transfer of CD4+ T cells or neutralization of macrophage colony-stimulating factor. Ex vivo assays demonstrated a pro-inflammatory state of PM from Sf mice and signs of excessive activation and exhaustion. In-depth immunophenotyping of Sf PM using single-cell chipcytometry and transcriptome analysis revealed upregulation of molecules involved in the initiation of innate and adaptive immune responses. Moreover, upon transfer to non-inflammatory environment or after injection of CD4+ T cells, PM from Sf mice reprogramed their functional phenotype, indicating remarkable plasticity. Interestingly, frequencies, and immune polarization of large and small PM subsets were dramatically changed in the FOXP3-deficient mice, suggesting distinct origin and specialized function of these subsets in inflammatory conditions. Our findings demonstrate the significant impact of Tregs in shaping PM identity and dynamics. A better understanding of PM function in the Sf mouse model may have clinical implication for the treatment of immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and other forms of immune-mediated enteropathies.
Highlights
Macrophages are tissue sentinels which continuously survey and maintain tissue homeostasis by providing host defense, immune regulation, and wound healing [1, 2]
Despite the fact that severe enteropathy and peritonitis represent common clinical manifestations and are a cause of death in children suffering from IPEX [8, 9], to date there is no data on peritoneal macrophages (PM) in the particular in vivo inflammatory environment caused by the absence of Treg-mediated immune control
It is well established that macrophages play important but complex roles in the regulation of autoimmune diseases and macrophage polarization in the context of inflammation is a topic of great interest [3, 4]
Summary
Macrophages are tissue sentinels which continuously survey and maintain tissue homeostasis by providing host defense, immune regulation, and wound healing [1, 2]. Their uncontrolled activation can result in tissue damage and progression of autoimmune diseases [3, 4], which makes them attractive therapeutic targets [5]. It has been indicated that regulatory T cells (Tregs) directly modulate differentiation and function of peritoneal macrophages (PM) [6]. IPEX syndrome is a rare multi-organ autoimmune disorder associated with neonatal onset and early mortality. It is caused by mutations in the gene encoding transcription factor Forkhead-box-P3 (FOXP3) which results in loss of functional Tregs. Despite the fact that severe enteropathy and peritonitis represent common clinical manifestations and are a cause of death in children suffering from IPEX [8, 9], to date there is no data on PM in the particular in vivo inflammatory environment caused by the absence of Treg-mediated immune control
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
