Glucocorticoids and neutrophil biology: impact on the development of resistance to glucocorticoid therapy

Neutrophils are the most abundant leukocytes in peripheral circulation and play a crucial role in combating infections and mediating inflammatory responses. Neutrophils are produced in bone marrow, have a short half-life in the blood, and are rapidly attracted to the tissues in response to infection or tissue damage. Glucocorticoids, stress hormones and potent anti-inflammatory agents, exert complex effects on neutrophils. While they generally suppress immune responses, glucocorticoids can paradoxically enhance neutrophil survival and function under certain conditions. This duality is evident in their ability to delay neutrophil apoptosis and to induce a shift of neutrophils from the marginated to the circulating pool, increasing the neutrophil presence in the bloodstream. Th17 cells, a subset of T-helper cells, recruit neutrophils to sites of infection and inflammation. In addition, neutrophils promote Th17 cell differentiation. Glucocorticoids can enhance Th17 differentiation and IL-17 production, exacerbating neutrophil accumulation. Nevertheless, in glucocorticoid-resistant diseases, including multiple sclerosis (MS), traumatic brain injury (TBI), and encephalomyelitis, Th17 cells and neutrophils contribute to persistent inflammation. This resistance complicates the treatment of autoimmune diseases and chronic inflammatory disorders, also in the central nervous system, where standard glucocorticoid therapy fails to mitigate symptoms effectively. In this context, we propose a mechanism for the development of resistance to GC driving by uncontrolled TH17 response and neutrophils induced by chronic stress. Understanding the interactions between neutrophils, Th17 cells, and glucocorticoids is essential for developing targeted therapies for diseases resistant to GC, such as MS, TBI, and encephalomyelitis.