NLRP3 inflammasome activation contributes to development of alopecia areata in C3H/HeJ mice

Abstract

Alopecia areata (AA) is an autoimmune non‐scarring hair loss disease. Recently, several reports have suggested that innate immune systems such as interferon‐α (IFN‐α)‐producing plasmacytoid dendritic cells and NOD‐like receptor family pyrin domain‐containing protein 3 (NLRP3) inflammasomes play a role in the pathogenesis of AA. However, critical studies about their involvement in the initiation of AA have not yet been reported. Therefore, we investigated the expression of innate immune cytokines in serum and skin, and examined the effect of a selective NLRP3 inhibitor, MCC950, on AA in C3H/HeJ mice, induced by transferring cultured skin‐draining lymph node cells. IFN‐α production was upregulated in lesions of AA‐affected mice, and interleukin‐1β in serum and skin was highly expressed before onset as well as postonset. Furthermore, MCC950 treatment prevented AA development and promoted hair growth in AA mouse models by reducing NLRP3 signalling and Th1/Tc1 chemokines and cytokines in the skin. These results suggest that NLRP3 inflammasome contributes to AA onset and chronicity, and NLRP3 inhibitor may be a potential therapeutic agent for AA.

The crosstalk between PTEN‐induced kinase 1‐mediated mitophagy and the inflammasome in the pathogenesis of alopecia areata

“…[29][30][31] In AA, in vitro and in vivo studies demonstrated the importance of the NLRP3 inflammasome in the pathogenesis of AA and suggested NLRP3 inhibitor as a potential therapeutic agent for AA. 20,21,32 Recently, there has been increasing evidence of the interrelationship between mitophagy and inflammasomes in human diseases. [12][13][14][15] The balanced activation of inflammasome-mitophagy may protect host immunity; however, the disproportion between inflammasomes and mitophagy can cause a chronic inflammatory cascade, and mitophagy induction and inflammasome inhibition can work as a therapeutic target in chronic inflammatory diseases.…”

“…Previous studies have revealed that inflammasomes are associated with several autoinflammatory and autoimmune diseases 29–31 . In AA, in vitro and in vivo studies demonstrated the importance of the NLRP3 inflammasome in the pathogenesis of AA and suggested NLRP3 inhibitor as a potential therapeutic agent for AA 20,21,32 . Recently, there has been increasing evidence of the interrelationship between mitophagy and inflammasomes in human diseases 12–15 .…”

Novel potential therapeutic targets of alopecia areata

“…Antigen-presenting cells (APCs) detect antigens with the help of the major histocompatibility complex (MHC) molecules on their surfaces. Unlike most human T cells that are MHC-restricted, γδ T cells do not need MHC activation to recognize antigens, as they are major players in innate immune responses along with inflammasomes and INF γ ( 23 – 25 ). Additionally, γδ T cells produce cytokines in the periphery and can be recruited to the lesion where they accumulate ( 26 ).…”