The interleukin-17 receptor plays a gender-dependent role in host protection against Porphyromonas gingivalis-induced periodontal bone loss.

Interleukin-17 (IL-17) is a proinflammatory cytokine secreted by the newly described CD4(+) Th17 subset, which is distinct from classic Th1 and Th2 lineages. IL-17 contributes to bone destruction in rheumatoid arthritis but is essential in host defense against pathogens that are susceptible to neutrophils. Periodontal disease (PD) is a chronic inflammatory condition initiated by anaerobic oral pathogens such as Porphyromonas gingivalis, and it is characterized by host-mediated alveolar bone destruction due primarily to the immune response. The role of IL-17 in PD is controversial. Whereas elevated IL-17 levels have been found in humans with severe PD, we recently reported that female C57BL/6J mice lacking the IL-17 receptor (IL-17RA(KO)) are significantly more susceptible to PD bone loss due to defects in the chemokine-neutrophil axis (J. J. Yu, M. J. Ruddy, G. C. Wong, C. Sfintescu, P. J. Baker, J. B. Smith, R. T. Evans, and S. L. Gaffen, Blood 109:3794-3802, 2007). Since different mouse strains exhibit differences in susceptibility to PD as well as Th1/Th2 cell skewing, we crossed the IL-17RA gene knockout onto the BALB/c background and observed a similar enhancement in alveolar bone loss following P. gingivalis infection. Unexpectedly, in both strains IL-17RA(KO) female mice were much more susceptible to PD bone loss than males. Moreover, female BALB/c-IL-17RA(KO) mice were defective in producing anti-P. gingivalis immunoglobulin G and the chemokines KC/Groalpha and MIP-2. In contrast, male mice produced normal levels of chemokines and anti-P. gingivalis antibodies, but they were defective in granulocyte colony-stimulating factor upregulation. This study demonstrates a gender-dependent effect of IL-17 signaling and indicates that gender differences should be taken into account in the preclinical and clinical safety testing of anti-IL-17 biologic therapies.

Interleukin-17: a novel inflammatory cytokine that bridges innate and adaptive immunity.

Interleukin-17 (IL-17A) is a pro-inflammatory cytokine that is primarily secreted from T lymphocytes, mediators of adaptive immunity. Recently, IL-17 was shown to be the defining cytokine of a new T helper subset termed "Th17." Discovery of the Th17 population was a groundbreaking discovery that has triggered major revisions of the prevailing paradigms in T cell biology. Although produced by T cells, IL-17 promotes expansion and recruitment of innate immune cells such as neutrophils, and also cooperates with TLR ligands, IL-1 beta, and TNF alpha to enhance inflammatory reactions and stimulate production of beta-defensins and other antimicrobial peptides. Its receptor, IL-17RA, is ubiquitously expressed and shares many features with classical innate immune receptors such as shared intracellular tail motifs and convergence on common inflammatory transcription pathways. The role of IL-17 in periodontal disease is still uncertain, since IL-17 has been shown to promote bone destruction in arthritis, but is nonetheless essential to protect the host from pathogens, including periodontopathic organisms. Recent evidence has shown that Th17 cells are more osteoclastogenic than other T helper subsets such as Th1 or Th2. Ablation of IL-17 signaling prior to onset of infection with Porphyromonas gingivalis increases susceptibility to periodontal bone loss, but this finding does not rule out the efficacy of therapeutic inhibition of IL-17 after onset of severe disease. IL-17 sits at the center of many complex diseases that integrate innate and adaptive immune mechanisms and requires careful study to maximize host protective effects and minimize host deleterious effects.

An essential role for IL-17 in preventing pathogen-initiated bone destruction: recruitment of neutrophils to inflamed bone requires IL-17 receptor-dependent signals.

IL-17 and its receptor are founding members of a novel family of inflammatory cytokines. IL-17 plays a pathogenic role in rheumatoid arthritis (RA)-associated bone destruction. However, IL-17 is also an important regulator of host defense through granulopoiesis and neutrophil trafficking. Therefore, the role of IL-17 in pathogen-initiated bone loss was not obvious. The most common form of infection-induced bone destruction occurs in periodontal disease (PD). In addition to causing significant morbidity, PD is a risk factor for atherosclerotic heart disease and chronic obstructive pulmonary disease (COPD). Similar to RA, bone destruction in PD is caused by the immune response. However, neutrophils provide critical antimicrobial defense against periodontal organisms. Since IL-17 is bone destructive in RA but a key regulator of neutrophils, we examined its role in inflammatory bone loss induced by the oral pathogen Porphyromonas gingivalis in IL-17RA-deficient mice. These mice showed enhanced periodontal bone destruction, suggesting a bone-protective role for IL-17, reminiscent of a neutrophil deficiency. Although IL-17RA-deficient neutrophils functioned normally ex vivo, IL-17RA knock-out (IL-17RA(KO)) mice exhibited reduced serum chemokine levels and concomitantly reduced neutrophil migration to bone. Consistently, CXCR2(KO) mice were highly susceptible to alveolar bone loss; interestingly, these mice also suggested a role for chemokines in maintaining normal bone homeostasis. These results indicate a nonredundant role for IL-17 in mediating host defense via neutrophil mobilization.