Keratinocytes control skin immune homeostasis through de novo–synthesized glucocorticoids

Abstract

Glucocorticoids (GC), synthesized by the 11β-hydroxylase (Cyp11b1), control excessive inflammation through immunosuppressive actions. The skin was proposed to regulate homeostasis by autonomous GC production in keratinocytes. However, their immunosuppressive capacity and clinical relevance remain unexplored. Here, we demonstrate the potential of skin-derived GC and their role in the regulation of physiological and prevalent inflammatory skin conditions. In line with 11β-hydroxylase deficiency in human inflammatory skin disorders, genetic in vivo Cyp11b1 ablation and long-term GC deficiency in keratinocytes primed the murine skin immune system resulting in spontaneous skin inflammation. Deficient skin GC in experimental models for inflammatory skin disorders led to exacerbated contact hypersensitivity and psoriasiform skin inflammation accompanied by decreased regulatory T cells and the involvement of unconventional T cells. Our findings provide insights on how skin homeostasis and pathology are critically regulated by keratinocyte-derived GC, emphasizing the immunoregulatory potential of endogenous GC in the regulation of epithelial immune microenvironment.

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

“…Whereas in MC903induced AD, which also causes a type 2 skin inflammation, local GC synthesis in keratinocytes was indeed induced, it did not appear to ameliorate the pathogenesis of AD (12). Additionally, formation of lymph node (LN)-resident CD44 + CD69 + T cells and OVA-specific immune responses in MC903-induced AD skin conditions did not show significant alterations in mice with deficient skin GC synthesis indicating that AD development and skin sensitization is not directly restricted by local skin GCs (12). In contrast, deficient keratinocyte GC synthesis in AD skin inflammation resulted in decreased IL-4 levels in skin associated with ameliorated itchiness.…”

“…As already mentioned, oxazolone-induced acute colitis failed to trigger LRH-1-regulated and TNFdependent GC synthesis in the intestine, similar to the lung where ovalbumin-induced airway hypersensitivity was ineffective in promoting local GC synthesis (5,13). Whereas in MC903induced AD, which also causes a type 2 skin inflammation, local GC synthesis in keratinocytes was indeed induced, it did not appear to ameliorate the pathogenesis of AD (12). Additionally, formation of lymph node (LN)-resident CD44 + CD69 + T cells and OVA-specific immune responses in MC903-induced AD skin conditions did not show significant alterations in mice with deficient skin GC synthesis indicating that AD development and skin sensitization is not directly restricted by local skin GCs (12).…”

“…Despite that, our understanding of how local GCmediated immunoregulatory circuits impact type 2 inflammation remains incomplete. Epithelial barrier-derived GCs were shown to exert individual roles in maintaining an autonomous and local immunoregulatory circuit in each of these tissues (1,5,12,13). As already mentioned, oxazolone-induced acute colitis failed to trigger LRH-1-regulated and TNFdependent GC synthesis in the intestine, similar to the lung where ovalbumin-induced airway hypersensitivity was ineffective in promoting local GC synthesis (5,13).…”

“…Active GCs can be either synthesized de novo from cholesterol with the final conversion catalyzed by 11bhydroxylase-1 (CYP11B1, Cyp11b1) or via reactivation from inactive cortisone, respectively 11-dehydrocorticosterone catalyzed by 11-b hydroxysteroid dehydrogenase 1 (HSD11B1, Hsb11b1). Mouse models of keratinocyte-specific Hsd11b1 or Cyp11b1 deficiency, resulting in abrogation of skin GC reactivation or de novo synthesis, revealed that the absence of either enzyme results in an imbalance of skin immune homeostasis and aggravation of inflammatory skin diseases (11,12).…”

“…However, recent evidence indicates a nonnegligible role of endogenous GCs in controlling T H 2 type responses, although their production is not strongly induced during these processes. Differently, atopic dermatitis (AD)-like skin inflammation as induced by the vitamin D3 analog MC903 was sufficient to promote local GC synthesis in keratinocytes, but the abrogation of local GC synthesis did not exacerbate AD-like skin inflammation (12). Although past research revealed the regulatory potential of extra-adrenal GCs in local immune responses at barrier tissues, current detailed insight into the respective processes is still limited.…”