Regulation of Tissue Immune Responses by Local Glucocorticoids at Epithelial Barriers and Their Impact on Interorgan Crosstalk

Abstract

The anti-inflammatory role of extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers is of increasing interest with regard to the search for alternatives to synthetic corticosteroids in the therapy of inflammatory disorders. Despite being very effective in many situations the use of synthetic corticosteroids is often controversial, as exemplified in the treatment of influenza patients and only recently in the current COVID-19 pandemic. Exploring the regulatory capacity of locally produced GCs in balancing immune responses in barrier tissues and in pathogenic disorders that lead to symptoms in multiple organs, could provide new perspectives for drug development. Intestine, skin and lung represent the first contact zones between potentially harmful pathogens or substances and the body, and are therefore important sites of immunoregulatory mechanisms. Here, we review the role of locally produced GCs in the regulation of type 2 immune responses, like asthma, atopic dermatitis and ulcerative colitis, as well as type 1 and type 3 infectious, inflammatory and autoimmune diseases, like influenza infection, psoriasis and Crohn’s disease. In particular, we focus on the role of locally produced GCs in the interorgan communication, referred to as gut-skin axis, gut-lung axis or lung-skin axis, all of which are interconnected in the pathogenic crosstalk atopic march.

Glucocorticoid Resistance: Interference between the Glucocorticoid Receptor and the MAPK Signalling Pathways

“…The synthesis and secretion of GCs is regulated by the central and local HPA axes [ 2 , 5 , 9 ], and dysregulation of these regulatory loops can result in GC excess or deficiency. Patients with Cushing syndrome present elevated endogenous systemic levels of cortisol due to pituitary ACTH-secreting or adrenal cortical ACTH-independent tumours [ 5 , 6 ].…”

“…Besides the adrenal GC production, certain tissues such as the thymus, intestine, brain, and skin, express functional equivalents of the HPA axis that allow for GC synthesis de novo [ 7 , 8 ]. This local GC production is increasingly recognized as a mechanism mediating rapid and critical control of immune activation [ 9 ].…”

Interactions between the Gut Microbiome, Lung Conditions, and Coronary Heart Disease and How Probiotics Affect These

“…Most of the interorgan communications between the gut and the lung occur via the bloodstream. Immune responses that exert an interorgan effect include antibody-activated T-lymphocytes that respond to the local presence of pathogens and toxins, as well as anti-inflammatory cytokines (glucocorticoids) that are produced to limit an inflammatory reaction to only the necessary level [ 32 ]. Glucocorticoids (GCs) generally have anti-inflammatory functions (the anti-inflammatory drug Dexamethasone is a synthetic glucocorticoid).…”

“…GCs are not only produced by the adrenal glands but also in smaller amounts by the epithelium of the gut and lung, where they downregulate local immune cell responses to avoid overreaction following a trigger. When pro-inflammatory tumor necrosis factor (TNF) is produced in the gut, it simultaneously stimulates the production of GCs, thus initiating the ‘brake’ that ensures a balanced inflammatory response [ 32 ]. Both the immunological defenses and the anti-inflammatory ‘brakes’ reach out beyond a locally infected area and enable the crosstalk between gut and lung.…”

“…As previously noted, IBD can be improved by SCFA supplementation. Both oral uptake of dietary fiber and of SCFA can contribute to airway homeostasis, as was demonstrated in mouse experiments [ 32 ]. In this context, it is no surprise that an association also exists between IBD and CVD; a cohort study in Taiwan indicated 27.5 times higher risk for peripheral arterial disease (PAD) in severe IBD patients [ 48 ].…”