Periodontitis is an inflammatory disease that causes destruction of the tooth-supporting tissues (periodontium) and typically affects adults. However, individuals with disorders affecting neutrophil recruitment to the periodontium, such as leukocyte adhesion deficiency Type I (LAD-I), develop severe periodontitis early in life. Understanding the pathogenic mechanisms of rare monogenic diseases, such as LAD-I, is important for two reasons: First, for effective treatment of patients with these specific disorders; second, these disorders represent real-life models to understand human biology and provide critical insights into common diseases. Periodontitis associated with LAD-I has been historically attributed to impaired neutrophil surveillance of the periodontal infection; however, it is unresponsive to antibiotics and/or mechanical removal of the tooth- associated biofilm, leads to premature loss of primary and permanent teeth, and can have serious adverse psychological and functional consequences in affected children. The overall objective of this project is to identify the fundamental underlying mechanism(s) of periodontitis associated with LAD-I (LAD-I periodontitis) and to propose rational novel treatment options. The overarching hypothesis is that LAD-I periodontitis is caused by dysregulated overexpression of the bone-resorptive cytokine IL-17 due to the disruption of a homeostatic mechanism known as the neutrostat. This is a regulatory feedback loop involving the IL-23-IL-17 axis that coordinates neutrophil recruitment and efferocytosis in tissues with neutrophil production in the bone marrow. The overarching hypothesis is supported by ample preliminary evidence, e.g., data revealing profound elevation of IL-23 and IL-17 in human LAD-I patients and in relevant mouse models of LAD-I, whereas considerably lower levels of these cytokines are detected in adult-type chronic periodontitis. This proposal comprises four specific aims and focuses on mouse model-based mechanistic and intervention studies.
In Aim 1, it is proposed that that reconstitution of LAD-I mice with transmigration-competent neutrophils restores normal IL-23 and IL-17 levels and inhibits bone loss.
Aim 2 investigates whether inhibition of apoptotic neutrophil phagocytosis (efferocytosis) replicates the LAD-I periodontitis phenotype.
Aim 3 is to determine whether synthetic agonist-induced activation of liver X receptor (normally activated in macrophages downstream of neutrophil efferocytosis) compensates for the lack of apoptotic neutrophils and restores IL- 23/IL-17 regulation in the gingiva of LAD-I mice.
Aim 4 involves the development of novel therapeutic approaches to LAD-I periodontitis through the use of small-molecule compounds targeting the IL-23-IL-17 pathway. This application, therefore, offers a fundamentally new insight into the mechanism of LAD-I periodontitis (and perhaps other disorders with impaired neutrophil recruitment) and has the potential to lead to innovative host-modulation approaches that can revolutionize the periodontal treatment of affected individuals.

Public Health Relevance

Leukocyte adhesion deficiency Type I (LAD-I) leads to destruction of periodontal bone and premature loss of primary and permanent teeth, and has therefore serious adverse psychological and functional consequences in children. The underlying etiology has been historically attributed to impaired neutrophil surveillance of the periodontal infection, although this form of periodontitis has proven unresponsive to antibiotics and/or mechanical removal of the tooth-associated biofilm. This project investigates the hypothesis that LAD-I- associated periodontitis is driven by the disruption of a key neutrophil homeostatic mechanism that leads to overproduction of a potent bone-resorptive cytokine (interleukin 17) and proposes novel treatments that can block this destructive process.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Chander, Preethi
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Dentistry/Oral Hygn
United States
Zip Code
Maekawa, T; Kulwattanaporn, P; Hosur, K et al. (2017) Differential Expression and Roles of Secreted Frizzled-Related Protein 5 and the Wingless Homolog Wnt5a in Periodontitis. J Dent Res 96:571-577
Hajishengallis, George; Korostoff, Jonathan M (2017) Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000 75:116-151
Kajikawa, Tetsuhiro; Meshikhes, Fatimah; Maekawa, Tomoki et al. (2017) Milk fat globule epidermal growth factor 8 inhibits periodontitis in non-human primates and its gingival crevicular fluid levels can differentiate periodontal health from disease in humans. J Clin Periodontol 44:472-483
Olsen, Ingar; Lambris, John D; Hajishengallis, George (2017) Porphyromonas gingivalis disturbs host-commensal homeostasis by changing complement function. J Oral Microbiol 9:1340085
Mitroulis, Ioannis; Chen, Lan-Sun; Singh, Rashim Pal et al. (2017) Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche. J Clin Invest 127:3624-3639
Moutsopoulos, Niki M; Zerbe, Christa S; Wild, Teresa et al. (2017) Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1. N Engl J Med 376:1141-1146
Mitroulis, Ioannis; Kang, Yoon-Young; Gahmberg, Carl G et al. (2014) Developmental endothelial locus-1 attenuates complement-dependent phagocytosis through inhibition of Mac-1-integrin. Thromb Haemost 111:1004-6