Myeloid corticoid receptors in CNS autoimmunity: Old targets for novel therapies

Abstract

Since the 1950s, glucocorticoids (GCs) have been the most widely employed drugs in the treatment of inflammatory and autoimmune disorders, such as multiple sclerosis (MS). Short-time application of high-dose GCs is the first line therapy for acute relapses of MS. Several clinical studies even suggest that prolonged GC pulsed therapy may slow down MS disease progression as well. However, a plethora of GC-associated side effects derived from the ubiquitous expression of the glucocorticoid receptor (GR) restricts the use of these drugs. Therefore, to assess the full potential of GCs new pharmacological formulations and more insights about their mechanisms of action are needed. For many years, T cells were proposed to be major targets of GCs in the treatment of neuroinflammation. In contrast, the relevance of myeloid cells for GC therapy is highlighted in this doctoral thesis. Using experimental autoimmune encephalomyelitis (EAE) as a mouse model of CNS autoimmunity, we directed GC therapy to the myeloid compartment by means of state-of-the-art inorganic-organic hybrid nanoparticles (IOH-NPs). Although IOH-NPs loaded with betamethasone (BNPs) modulated both T cell survival and macrophage activation in vitro, in vivo BNPs selectively targeted myeloid cells. Moreover, BNPs achieved a therapeutic efficacy comparable to free GCs in the treatment of EAE. In this study BNPs were also proposed as an alternative to circumvent GC-derived side effects, however our data did not provide conclusive information in this respect yet. Additionally, the roles of the two different GC-responsive nuclear receptors, the GR and the mineralocorticoid receptor (MR), were investigated in myeloid cells. In this cell compartment, GCs can act either via the GR in a deactivating manner, or via the MR promoting a pro-inflammatory state. Hence, we hypothesized that altering the balance between the GR and the MR might influence the course of EAE. Indeed, mice selectively devoid of MR in myeloid cells developed a milder EAE disease course compared to their littermate controls, and presented with a lower degree of demyelination. Consistent with these results, monocytes/macrophages exhibited a M2 phenotype in both the CNS and the periphery, and the proportion of reactive microglia in the spinal cord was reduced as well. Furthermore, our experiments revealed that, in consequence of the general myeloid anti-inflammatory state, Treg cell numbers increased in secondary lymphoid organs, where cytokine release by effector T cells was consequently impaired. Taken together, this study provides evidence of the important implications of myeloid cells in the response to GCs during autoimmune inflammation, and supports the targeted delivery to the myeloid compartment as an alternative to improve the therapeutic features of synthetic GCs.