Fig. 2

RANKL in immunity. a RANKL–RANK interaction in the development of the thymus. RANKL is produced by LTi cells, T cells, and iNKT cells and interacts with the RANK expressed on mTECs. This interaction induces the expression of Aire, resulting in the expression of TSAs on MHC molecules. The TSA–MHC complex is necessary for negative selection, the key process for establishing self-tolerance. b RANKL–RANK interaction in the lymph node development. Lymph node development begins with the interaction between LTi cells and LTo cells. LTα1β2 is expressed by LTi cells and interacts with LTβR on LTo cells, which in turn leads to the expression of RANKL on LTo cells. The expressed RANKL stimulates LTi cells to induce more LTα1β2, forming a positive feedback loop. With the stimulation of LTα1β2, some LTo cells mature into MRCs. The RANKL on LTo cells and MRCs binds to the RANK on lymphatic endothelial cells, resulting in the recruitment of macrophages. c RANKL–RANK interaction in the gastrointestinal tract. (Left) ILC3s interact with each other through RANKL and RANK. The interaction leads to the decrease of the proliferation and IL-17/IL-22 production of these cells, resulting in the suppression of excessive inflammation. (Right) RANKL–RANK interaction in M cell development. Mesenchymal cells beneath the epithelium of the gastrointestinal tract express RANKL and interact with RANK–expressing epithelial cells. These cells differentiate into morphologically and functionally unique cells called M cells. These cells enable the transfer of antigens from the lumen of gastrointestinal tract to DCs, leading to IgA production. d RANKL–RANK interaction in the skin. Keratinocytes express RANKL upon UV–irradiation. The RANKL binds to LCs in the skin. These LCs contribute to the generation of Treg cells, which decrease the skin inflammation and resolution of dermatitis in psoriasis and atopic dermatitis. e RANKL–RANK interaction in the CNS inflammation. (Left) T_H17 cell cells induce the CCL20 expression of astrocytes at the blood–brain barrier via RANKL–RANK signaling. CCL20 recruits CCR6-expressing cells, including T_H17 cell cells. These accumulated cells penetrate the barrier and infiltrate into the CNS to elicit inflammation. (Right) In the context of ischemic stroke, dead cells in the brain release DAMPs, which are recognized by TLRs. TLR stimulation of microglial cells leads to the production of pro-inflammatory cytokines including IL-6 and TNF-α, leading to inflammation and further cell death. RANKL–RANK signal in the microglial cells inhibits the production of these cytokines, resulting in the protection of the brain. RANKL receptor activator of NF-κB ligand, RANK receptor activator of NF-κB, LTi cell lymphoid tissue inducer cell, iNKT cell invariant natural killer T cell, mTEC medullary thymic epithelial cell, Aire autoimmune regulator, TSA tissue-specific antigen, MHC major histocompatibility complex, LTo cell lymphoid tissue organizer cell, LT lymphotoxin, LTβR lymphotoxin β receptor, MRC marginal reticular cell, ILC3 group 3 innate lymphoid cell, IL interleukin, DC dendritic cell, UV ultra violet, LC Langerhans cell, Treg cell regulatory T cell, CNS central nervous system, T_H17 cell T helper 17 cell, CCL20 C-C motif chemokine ligand 20, CCR6 C-C motif chemokine receptor 6, DAMP damage-associated molecular pattern, TLR Toll-like receptor