Myeloid inflammatory cells (macrophages, dendritic cells (DC), and infiltrating monocytes) are long lived, TLR4+ cells strategically poised along portals of entry where they perform functions of vital importance to the host. These cells are active participants in innate immunity and orchestrate the transition to and propagation of the adaptive arm of the immune response. Along with these important functions, myeloid inflammatory cells have been implicated in periodontal pathogenesis due to their capacity to secrete copious amounts of proinflammatory cytokines/chemokines and other inflammatory mediators and by serving as osteoclast precursors. Thus modulation of their destructive potential is of great therapeutic interest. While significant progress has been made in elucidating the mechanisms associated with periodontal pathosis, very little is known regarding the role of microRNA (miRNA) in this process. miRNA exerts significant biological effects upon many normal and abnormal cellular functions and it has become increasingly clear that it plays a key role in development and function of the immune response. Moreover, recent reports have begun to highlight their potential value as diagnostic markers. Unfortunately, significant gaps in knowledge are evident regarding the identification and characterization of miRNA in periodontal disease. This is important given the increasing body of evidence implicating dysregulated miRNA profiles in immune-mediated disorders. Our preliminary in-vitro and in-vivo studies have identified candidate miRNAs predicted to target genes linked to myeloid inflammatory cell and osteoclast differentiation and function. These candidate miRNAs were identified from primary myeloid inflammatory cell cultures challenged with periopathic LPS and from gingival tissue specimens derived from periodontally healthy and diseased subjects. As inflammation and bone loss, hallmarks of periodontal disease are mediated in part by the long-lived myeloid inflammatory cell pool, studies focused on the identification and validation of factors selectively modulating their destructive capacity, will advance scientific knowledge and identify new avenues of research and therapy. This proposal seeks to functionally validate candidate miRNAs as modulators of differentiation and function in myeloid inflammatory cells and osteoclasts. Using a systematic approach we will begin by determining the effects of overexpression and knockdown of our candidate miRNAs on myeloid inflammatory cell and osteoclast differentiation. We will also determine the effects on key cellular functions linked to periodontal inflammation and osteoclastogenesis. Thus, this proposal seeks to fill voids in knowledge regarding the role of miRNA in periodontal pathogenesis and provide a basis for the development of animal models that can be genetically manipulated to characterize miRNAs demonstrating significant promise. Ultimately, the goal of which is to identify novel and therapeutically beneficial drug targets that will enhance current treatment modalities.

Public Health Relevance

In the oral cavity, excessive inflammation in response to bacteria can lead to periodontal disease and result in tooth loss. Thus, appropriate control of this inflammatory process is of great therapeutic interest. The focus of our study is to investigate the regulation of endogenous molecules triggering this reaction to prevent excessive inflammation and tooth loss. Knowledge to be gained from this study will be of value to medicine and dentistry.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Lumelsky, Nadya L
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University of Illinois at Chicago
Schools of Dentistry
United States
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Naqvi, Afsar R; Brambila, Maria F; Martínez, Gloria et al. (2018) Dysregulation of human miRNAs and increased prevalence of HHV miRNAs in obese periodontitis subjects. J Clin Periodontol :
Naqvi, Afsar R; Shango, Jennifer; Seal, Alexandra et al. (2018) Viral miRNAs Alter Host Cell miRNA Profiles and Modulate Innate Immune Responses. Front Immunol 9:433
Zhong, Sheng; Naqvi, Afsar; Bair, Eric et al. (2017) Viral MicroRNAs Identified in Human Dental Pulp. J Endod 43:84-89
Naqvi, Afsar Raza; Zhong, Sheng; Dang, Hong et al. (2016) Expression Profiling of LPS Responsive miRNA in Primary Human Macrophages. J Microb Biochem Technol 8:136-143
Naqvi, Afsar Raza; Fordham, Jezrom B; Nares, Salvador (2016) MicroRNA target Fc receptors to regulate Ab-dependent Ag uptake in primary macrophages and dendritic cells. Innate Immun 22:510-21
Fordham, Jezrom B; Guilfoyle, Katherine; Naqvi, Afsar Raza et al. (2016) MiR-142-3p is a RANKL-dependent inducer of cell death in osteoclasts. Sci Rep 6:24980
Kulkarni, Varun; Naqvi, Afsar Raza; Uttamani, Juhi Raju et al. (2016) MiRNA-Target Interaction Reveals Cell-Specific Post-Transcriptional Regulation in Mammalian Cell Lines. Int J Mol Sci 17:
Naqvi, Afsar Raza; Fordham, Jezrom B; Ganesh, Balaji et al. (2016) miR-24, miR-30b and miR-142-3p interfere with antigen processing and presentation by primary macrophages and dendritic cells. Sci Rep 6:32925
Fordham, Jezrom B; Naqvi, Afsar R; Nares, Salvador (2015) miR-24 Regulates Macrophage Polarization and Plasticity. J Clin Cell Immunol 6:
Fordham, Jezrom B; Naqvi, Afsar R; Nares, Salvador (2015) Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity. J Leukoc Biol 98:195-207

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