CD38 signaling in aging-associated immune responses induced by oral pathogens

The aging population has increased globally, leading to an increased incidence of aging-related comorbidities including periodontitis. Our long-term goal is to develop effective new therapies to alleviate periodontal inflammatory bone loss associated with aging-related periodontitis and help prolong the healthspan of human beings. It is well-known that nicotinamide adenine dinucleotide (NAD+) plays essential roles in the healthspan of human beings. Previous studies demonstrated that a decline of NAD+ in the aged population contributes to the pathogenesis of various aging-associated diseases, including type II diabetes and Alzheimer’s disease. Moreover, CD38 (an inflammatory marker and an enzyme active in degrading NAD+) enhanced in the aged population. Inhibition of CD38 by a specific inhibitor (78c) reversed age-related NAD+ decline and increased the lifespan and healthspan of naturally aged mice. However, significant knowledge gaps exist. It is unclear how oral bacterial pathogens influence aging-associated immune responses, and how the CD38 signaling pathway regulates aging-associated immune responses induced by oral bacterial pathogens. The goal of this application is to define how oral pathogens affect aging-associated immune responses and whether inhibition of CD38 can attenuate inflammatory bone loss and alleviate aging-associated immune responses induced by oral pathogens. Our preliminary results are the first to show that the oral pathogen Aggregatibacter actinomycetemcomitans (Aa) or Porphyromonas gingivalis (Pg), enhanced CD38 levels and significantly decreased the NAD+ levels in old murine bone marrow-derived monocyte and macrophages (BMMs), compared with control levels derived from young murine BMMs. Moreover, inhibition of CD38 by 78c reduced CD38 levels and reversed the decline of NAD+ in murine BMMs infected with Aa. Additionally, in murine BMMs infected with Aa, treatment with 78c enhanced the mRNA and protein levels of pro-longevity genes (Sirtuin1, PARP-1, and NAMPT) and superoxide dismutase1 (SOD1, an antioxidant enzyme), but reduced NADPH oxidase1 (Nox1) expression. Furthermore, treatment with 78c attenuated IL-1b, IL-6, and TNF-a cytokine levels induced by Aa and inhibited osteoclastogenesis induced by RANKL. Thus, we hypothesize that inhibition of CD38 by 78c is a novel therapeutic strategy to treat aging-associated periodontitis. Our specific aims are as follows: 1) We will determine if murine BMMs derived from old mice have higher levels of CD38 and lower levels of NAD+ with or without Aa or Pg infection, when compared with the murine BMMs derived from young mice, and if knockdown or inhibition of CD38 in vitro in BMMs can reduce CD38, increase NAD+ and NAD+ biosynthesis salvage pathway (Sirtin1, PARP-1, NAMPT) signaling, and reduce oxidative stress induced by Aa or Pg. 2) We will generate a periodontitis animal model in mice, and determine if treatment with the CD38 specific inhibitor (78c) in vivo can reduce CD38, attenuate periodontal inflammatory bone loss, decrease oxidative stress, enhance NAD+, and increase Sirtin1, PARP-1, NAMPT genes in the tissues, compared with controls. Project Number: 1R21DE033977-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Hong Yu | Institution: MEDICAL UNIVERSITY OF SOUTH CAROLINA, CHARLESTON, SC | Award Amount: $226,500 | Activity Code: R21 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11129187