Neutrophils, IL-17 and oral microbiota in periodontitis

Th17 response has the ability to induce migration of neutrophils from the bloodstream into inflamed tissues. Neutrophils form the important part of immune defense and as such are equipped with a number of anti-microbial and pro-inflammatory measures. However, as in the case of other immune effectors their action may also have the darker side – collateral injuries to the surrounding environment. Such immune-mediated bystander damages underlie the pathology of periodontitis which is the inflammatory disease afflicting gingival tissue. I have read very interesting publication that describes how the intricate interplay between neutrophils and IL-17 cytokine may regulate periodontitis development.

The link:

Periodontitis is a disease that inflicts neutrophil-mediated inflammatory lesions to the tooth-supportive tissue which may result in loosening and loss of teeth. Old mice just like old humans are prone to develop periodontitis. Del -1 is a negative regulator of neutrophil extravasation which is known to be expressed by endothelial cells (cells that line blood vessels). Authors initially explored Del-1 expression pattern in various age groups as the association between the age and the disposition to excessive inflammation is well known. They concluded that Del-1 level in the gingival tissue of older mice represented only a small portion (~25%) of Del-1 amount found in younger mice. They also found that the decrease in Del-1 expression correlated with more pronounced tooth bone loss and the enhanced neutrophil influx to gingiva. The Del-1/neutrophils/bone loss relationship was confirmed by using Del-1 deficient mice. Apart from that it was shown that the increase in gingival neutrophil infiltration mediated by the deletion of Del-1 could be counteracted by knocking out LFA-1 which is a positive regulator involved in neutrophil tissue migration.

Del-1 deletion seemed to augment the local Th17 response as Del-1 deficient mice expressed more IL-17A (IL-17C and IL-17F were also increased) as well as p40 and p19 (subunits of IL-23 which is strong Th17 response inducer). Remarkably, the analysis of IL-17RA-deficient mice has shown that inflammatory bone loss characteristic for periodontal injuries was completely abolished when there was no IL-17 signaling (interestingly, there was no difference between IL17RA-deficient strain and combined IL-17RA/Del-1 mutant). IL-17RA deletion also enhanced Del-1 expression in gingival tissues. Investigators confirmed the link between lack of IL-17 signaling and increase in Del-1 amount by neutralization method (injection of monoclonal anti-IL17 antibody to gingiva) and bone marrow chimeras experiments. The last approach revealed that the lack of IL-17RA on non-hematopoietic cells was important in regulating Del-1 expression. Finally, authors explored whether administration of Del-1 into inflamed gingival tissues could have the therapeutic potential

Beyond results discussed above this publication contains data on how genetic background that underlies quantitative aspects of neutrophil migration into gingiva may influence the oral microbiota. These data are somewhat counter-intuitive (as it is sometimes the case for things happening at mucosal surfaces). The leading theme of this paper is that Del-1 down-regulation or absence promotes the enhanced neutrophil infiltration and augments inflammatory-mediated tooth bone loss. However, Del-1 deletion (and hence more gingival neutrophils, which after all are thought to be cells with anti-microbial properties) actually stimulates more bacterial growth. This not just one odd result, because when Del-1 deletion is combined with LFA-1 knockout (a positive regulator of neutrophil extravasation) or IL-17RA knockout (removing thus the important part of signaling involved in the neutrophil influx) the number of oral anaerobic bacteria goes back to normal values. Thus to sum up, the excessive inflammation seems to boost but not to restrict the growth of oral microbiota. Authors do not follow this observation but I think it is very interesting phenomenon.

Eskan, M., Jotwani, R., Abe, T., Chmelar, J., Lim, J., Liang, S., Ciero, P., Krauss, J., Li, F., Rauner, M., Hofbauer, L., Choi, E., Chung, K., Hashim, A., Curtis, M., Chavakis, T., & Hajishengallis, G. (2012). The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss Nature Immunology, 13 (5), 465-473 DOI: 10.1038/ni.2260

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