Oral 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

Novel mineralocorticoid receptor signalling mechanisms and the regulation of inflammation (#31)

Gregory S Ong 1 2 , Timothy J Cole 3 , Gregory H Tesch 4 , Jennifer H Dowling 5 , James Morgan 1 , Ashley Mansell 6 , Peter J Fuller 1 , Morag J Young 1 7
  1. Centre for Endocrinology and Metabolism, Husdon Institute of Medical Research, Clayton, VIC, Australia
  2. Fiona Stanley Hospital, Murdoch, WA, Australia
  3. Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
  4. Medicine (Monash Health), Monash University, Clayton, VIC, Australia
  5. School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons Ireland, Dublin, Ireland
  6. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  7. Baker Heart & Diabetes Institute, Melbourne, VIC, Australia

The mineralocorticoid receptor (MR) is expressed in numerous cell types which do not participate in its classically described function of salt homeostasis. Chronic excess MR activation in cardiovascular cells results in inflammation and fibrosis, manifesting as an excess risk of cardiovascular disease in primary hyperaldosteronism compared to blood pressure-matched controls. In immune cells such as macrophages, MR signalling influences the response to injury. Mice with MR-null macrophages exposed to excess mineralocorticoids are relatively protected from cardiac fibrosis and dysfunction compared to wild type controls. MR-null tissue macrophages tend to exhibit more anti-inflammatory and pro-reparative behaviours compared to wild type macrophages. MR exerts effects on macrophages via two broad mechanisms - canonical MR signalling as a transcription factor and direct regulator of gene expression, or non-canonical MR signalling via intracellular “second messenger” cascades. The former is critical for renal fluid and electrolyte handling. However, the importance of different MR signalling mechanisms on macrophage behaviour and inflammation is not known. To investigate this, we developed novel macrophage cell lines and transgenic mice with a mutant macrophage MR incapable of DNA binding. Canonical MR action was responsible for direct mineralocorticoid-induced gene transcription or modulating the Phorbol 12-myristate 13-acetate (PMA)-induced transcription of inflammatory cytokines and fibrotic factors. Non-canonical MR action was important for lipopolysaccharide (LPS-), but not PMA-induced JNK activation. Interestingly, the macrophage transcriptional response to LPS required intact non-canonical MR signalling irrespective of the presence of mineralocorticoid. Analysis of the MR target gene and profibrotic factor Mmp12 identified promoter elements that are regulated by combined MR/MAPK/JNK signalling. An 8-day deoxycorticosterone/salt challenge of uninephrectomised male mice found that non-canonical MR signalling is sufficient for development of cardiac inflammation. Overall, MR signalling regulates pro-inflammatory macrophage behaviour via canonical and non-canonical mechanisms. Further, there is evidence of a novel link between LPS, MR and MAPK. 

  1. Ong, G., Cole, T. J., Tesch, G. H., Morgan, J., Dowling, J. K., Mansell, A., Fuller, P. J., & Young, M. J. (2020). Novel mineralocorticoid receptor mechanisms regulate cardiac tissue inflammation in male mice. The Journal of Endocrinology, 246(2), 123–134.