PUBLICATION
The mineralocorticoid receptor plays a crucial role in macrophage development and function
- Authors
- Faught, E., Schaaf, M.J.M.
- ID
- ZDB-PUB-230820-48
- Date
- 2023
- Source
- Endocrinology 164(10): (Journal)
- Registered Authors
- Schaaf, Marcel J. M.
- Keywords
- Mineralocorticoid receptor, cortisol, glucocorticoids, innate immune system, macrophages, zebrafish
- MeSH Terms
-
- Animals
- Eplerenone/pharmacology
- Glucocorticoids
- Humans
- Hydrocortisone*/pharmacology
- Inflammation
- Macrophages
- Receptors, Mineralocorticoid*/genetics
- Zebrafish
- PubMed
- 37597174 Full text @ Endocrinology
Citation
Faught, E., Schaaf, M.J.M. (2023) The mineralocorticoid receptor plays a crucial role in macrophage development and function. Endocrinology. 164(10):.
Abstract
Stress and the attendant rise in glucocorticoids (GCs) results in a potent suppression of the immune system. To date, the anti-inflammatory role of GCs, via activation of the glucocorticoid receptor (GR), has been well-characterized. However, cortisol, the primary GC in both fish and humans, also signals through the high-affinity mineralocorticoid receptor (MR), of which the immunomodulatory role is poorly understood. Here we tested the hypothesis that MR is a key modulator of leukocyte function during inflammation. Using transgenic MR knockout (MRKO) zebrafish with fluorescently labelled leukocytes, we show that a loss of MR results in a global reduction in macrophage number during key development stages. This reduction was associated with impaired macrophage proliferation and responsivity to developmental distribution signals, as well as increased susceptibility to cell death. Using a tail fin amputation in zebrafish larvae as a model for localized inflammation, we further showed that MRKO larvae display a reduced ability to produce more macrophages under periods of inflammation (emergency myelopoiesis). Finally, we treated wildtype larvae with an MR antagonist (eplerenone) during definitive hematopoiesis, when the macrophages had differentiated normally throughout the larvae. This pharmacological blockade of MR reduced the migration of macrophages towards a wound, which was associated with reduced macrophage Ccr2 signalling. Eplerenone treatment also abolished the cortisol-induced inhibition of macrophage migration, suggesting a role for MR in cortisol-mediated anti-inflammatory action. Taken together, our work reveals that MR is a key modulator of the innate immune response to inflammation under both basal and stressed conditions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping