Inflammasome targeting for periodontitis prevention is sex dependent
Abstract
Inflammasome initiates inflammation via the maturation of interleukin-1 beta (IL-1β). Periodontitis is a prevalent, male-biased disease characterized by inflammation-driven bone loss, yet the mechanism(s) of this sex bias is unknown. This study explored whether enhanced inflammasome represents a causal mechanism for this bias. Analyses of three separate human studies (>6,200 samples) show that males have significantly higher IL-1β in the gingival crevicular fluid than females during health and periodontitis. This pattern is experimentally reproduced with different versions of the ligature-induced periodontitis mouse model where males show greater IL-1β secretion than females. The inflammasome drives bone resorption in males but not females as revealed by analyses of inflammasome gene-deletion mice. Pharmacologic treatment with a caspase-1/4 inhibitor reduces inflammatory cell infiltration, dampens osteoclastogenesis signaling (via the receptor activator of nuclear factor-kappa B pathway), and prevents bone resorption in males but not females during experimental periodontitis. While ovariectomized females show no change in their nonresponsiveness to caspase-1/4 inhibition, orchiectomized males no longer respond to the inhibition, suggesting the importance of an intact male reproductive system in the mediation of this inhibition. Thus, our study identifies inflammasome activation as causal for male-biased experimental periodontitis and supports sex-stratified studies to foster future advancement of inflammasome therapeutics in periodontics.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (29)
Tomaz Alves
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Karen V. Swanson
Division of Infectious Diseases, School of Medicine, University of North Carolina
Mustafa S. Girnary
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Marcelo Freire
Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego
Kevin Moss
Department of Biostatistics and Health Data Science, School of Medicine, University of Indiana
Kimon Divaris
Department of Pediatric and Public Health, Adams School of Dentistry, University of North Carolina
James Beck
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Pollyana Coelho Pessoa Santos
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
W. June Brickey
John A. Wrobel
Lineberger Comprehensive Cancer Center, University of North Carolina
Heidi Yeigi Min
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Manaal Syed
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Thiago Morelli
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
William T. Seaman
National Institute of Dental and Craniofacial Research, National Institutes of Health
John S. Preisser
Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina
Di Hu
Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina
Hannah Preisser
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Natalia Makhanova
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Cristiano Susin
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Nishma P. Vias
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina
Maya Styner
Division of Endocrinology and Metabolism, School of Medicine, University of North Carolina
Shaoping Zhang
Flavia Queiroz Pirih
Division of Regenerative and Reconstructive Sciences, School of Dentistry, University of California Los Angeles
Jia Chang
Harvinder Singh Gill
Department of Chemical and Biomolecular Engineering, North Carolina State University
Adam D. Lietzan
Department of Biomedical Sciences, Adams School of Dentistry, University of North Carolina
Jennifer Webster-Cyriaque
National Institute of Dental and Craniofacial Research, National Institutes of Health
Jenny P. Y. Ting
Lineberger Comprehensive Cancer Center, University of North Carolina
Julie T. Marchesan
Department of Periodontology, Endodontics, and Dental Hygiene, Adams School of Dentistry, University of North Carolina