IL-33 Exacerbates Periodontal Disease through Induction of RANKL

Abstract

Cytokines mediate the balance between protective and destructive immunity in periodontitis. We sought to investigate the role of IL-33 in periodontitis. The expression of IL-33 in gingival tissue from healthy controls (n = 10) and patients with chronic periodontitis (n = 17) was investigated. Based on a murine model of periodontal disease, the function of IL-33 was determined first by administration of exogenous IL-33 and second by inhibition of IL-33 signaling using mice deficient in the IL-33 receptor ST2. Alveolar bone level, serum antibody, and lymphocyte responses were assessed in the murine model. Expression of IL-33 and ST2 was elevated in gingival tissues from patients with chronic periodontitis as compared with healthy tissues (P < 0.05). Similarly, Il33 expression was higher in periodontal tissues of Porphyromonas gingivalis-infected mice as compared with sham-infected controls (P < 0.05). IL-33 treatment of P. gingivalis-infected mice significantly exacerbated alveolar bone loss when compared with infection or IL-33 treatment alone (P < 0.001). Conversely, P. gingivalis infection-induced alveolar bone loss was attenuated in mice lacking ST2. The percentages of T and B lymphocytes expressing nuclear factor κB ligand (RANKL) in the gingival tissues and T lymphocytes expressing RANKL in the cervical draining lymph nodes were higher in IL-33-treated P. gingivalis-infected mice versus phosphate buffered saline-treated P. gingivalis-infected controls (all P < 0.001). Targeting the RANKL pathway by osteoprotegerin administration abrogated periodontal bone destruction in P. gingivalis-infected, IL-33-treated mice. These data demonstrate a previously unrecognized role for IL-33 in exacerbating bone loss in a RANKL-dependent manner in the context of bacterial infection and suggest that this pathway may be amenable to manipulation as a novel therapeutic target in periodontitis.

Interleukin-33 and RANK-L Interplay in the Alveolar Bone Loss Associated to Periodontitis

“…IL-33 expression in CP in human has recently been described by Malcolm et al in gingival epithelial cells and our results confirmed this observation [20]. This is of particular interest because differences of IL-33 expression in skin have been reported between species [35].…”

“…In a rat model of ligature induced-periodontitis, IL-33 expression was upregulated concomitantly to RANK-L [19]. In human, high IL-33 overexpression was recorded in the gingiva of patients affected by CP and may act as a triggering factor for the recruitment of B and T lymphocytes expressing RANK-L [20]. But in gingival crevicular fluid (an inflammatory exudate collected in the periodontal pocket) conflicting results regarding IL-33 levels have been reported in patients affected by CP [21–23].…”

Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis

“…IL-33 administration exacerbates collagen-induced and K/BxN serum-mediated murine arthritis, and disease severity is reduced in mice treated with sST2-Fc fusion protein or anti-IL-33 monoclonal antibody [6–8]. Extracellular IL-33 is a critical enhancer of tumor necrosis factor (TNF)-induced RA synovial fibroblast activation [9] and could activate osteoclastogenesis [10, 11]. In patients with RA, biomarker studies have suggested that the serum level of IL-33 could reflect clinical activity [12] and disease severity, or predict carotid plaque progression [13].…”

<b>Increases in IL-33 production by fimbriae and lipopeptide from </b><i><b>Porphyromonas gingivalis</b></i><b> in mouse bone marrow-derived dendritic cells via Toll-like receptor </b><b>2 </b>

“…Accordthelium from patients with chronic periodontitis expresses IL-33, but scarcely in that from healthy individuals (11,24). We reported previously that the contaminant related to TLR2 activity in the P. gingivalis LPS fraction is lipoprotein (14).…”