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Published on: November 4, 2016
CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects
Angela J T Bosch1, Lena Keller1, Laura Steiger1
1Department of Biomedicine, University of Basel, Basel, Switzerland.
Aims/Hypothesis:
Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition.
Methods:
We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet.
Results:
CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1β+ islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1β as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1β prior to glucose stimulation in mice lacking macrophages.
Conclusions/Interpretation:
Macrophages and macrophage-derived factors, such as IL-1β, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease.
Data Availability:
The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 ).
Insights
Colony stimulating factor 1 receptor (CSF1R) inhibition alters immune cell composition and impacts glucose metabolism. Macrophage depletion improves insulin sensitivity but impairs insulin secretion, highlighting IL-1β
Area of Science:
- Immunology and Metabolism
- Cell Biology
- Endocrinology
Background:
- Colony stimulating factor 1 (CSF1) influences macrophage behavior, which affects glucose metabolism.
- The role of CSF1 signaling in glucose homeostasis and its therapeutic potential remain unclear.
Purpose of the Study:
- To investigate tissue immune cell composition after CSF1 receptor (CSF1R) inhibition.
- To determine the metabolic consequences of CSF1R inhibition on glucose homeostasis.
Main Methods:
- Mice were treated with a CSF1R inhibitor (PLX5622) or a control diet.
- Immune cell populations were analyzed using flow cytometry.
- Metabolic effects were assessed via hyperinsulinemic-euglycemic clamps and insulin secretion assays.
Main Results:
- CSF1R inhibition depleted macrophages, increasing eosinophils and innate lymphoid cells.
- Hepatic insulin sensitivity improved, but insulin secretion was impaired.
- Interleukin-1β (IL-1β) from islet macrophages was identified as a key factor in insulin secretion.
Conclusions:
- Macrophages and IL-1β are critical for physiological insulin secretion.
- CSF1R inhibition has complex effects on immune cells and glucose metabolism.
- Understanding these interactions is vital for developing immune-modulatory therapies for metabolic diseases.
