CD38 Inhibitor 78c Restores NAD+ and Cuts Inflammation in Aged Immune Cells
Blocking CD38 with compound 78c replenishes NAD+, slashes inflammatory cytokines, and reduces oxidative stress in old macrophages infected with oral pathogens.
Summary
Aging macrophages show dramatically elevated CD38 — an enzyme that degrades NAD+ — after infection with periodontal pathogens, driving NAD+ depletion and oxidative stress. Researchers at MUSC found that treating old murine bone marrow-derived macrophages with the selective CD38 inhibitor 78c restored NAD+ levels, reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), lowered reactive oxygen species and NADPH oxidase 1, and boosted five antioxidant enzymes. Notably, the elevated CD38 in aged macrophages was not simply a product of stronger immune signaling — old cells actually showed delayed and weaker NF-κB, PI3K, and MAPK activation, yet still upregulated CD38 more than young controls, pointing to an age-specific dysregulation of NAD+ metabolism as a tractable therapeutic target in aging-related periodontitis.
Detailed Summary
Periodontal disease is disproportionately severe in older adults, yet the molecular mechanisms linking aging-associated immune dysfunction to worsened oral infection remain incompletely understood. A key suspect is CD38, a membrane-bound NAD+ glycohydrolase that rises with age and accelerates the NAD+ depletion already characteristic of aging tissues. This study from the Medical University of South Carolina investigated whether CD38 upregulation in aged macrophages is responsible for the exaggerated inflammatory and oxidative damage seen after oral pathogen infection, and whether pharmacological CD38 inhibition could reverse these deficits.
The research team isolated bone marrow-derived macrophages (BMMs) from young (3-month-old) and old (18–20-month-old) mice and infected them with two clinically relevant periodontal pathogens: Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg). CD38 protein was undetectable in uninfected cells of either age group, but 24 hours post-infection, old BMMs showed 3.1-fold (Aa) and 2.3-fold (Pg) higher CD38 than young controls, accompanied by approximately 43% lower NAD+ levels. Crucially, Western blot time-course analysis (1–24 h) revealed that old macrophages actually displayed delayed and attenuated activation of NF-κB, PI3K, ERK, JNK, and p38 MAPK compared to young cells, and pro-inflammatory cytokine levels (IL-1β, IL-6, TNF-α) were statistically similar between age groups at 24 h. This decoupling demonstrates that elevated CD38 in aged macrophages is not simply downstream of a stronger inflammatory signal — it represents an independent, age-driven dysregulation.
To probe therapeutic intervention, old BMMs were pre-treated with 78c, a potent and selective small-molecule CD38 inhibitor, before Aa or Pg infection. 78c significantly reduced CD38 protein expression and restored NAD+ to levels comparable to young infected controls. Concurrently, 78c substantially attenuated IL-1β, IL-6, and TNF-α secretion, reduced intracellular reactive oxygen species (ROS) and NADPH oxidase 1 (Nox1) expression, and markedly upregulated five antioxidant enzymes: superoxide dismutase 1 (Sod1), glutathione peroxidase 4 (Gpx4), peroxiredoxin 1 (Prdx1), thioredoxin reductase 1 (Txnrd1), and catalase (Cat). These coordinated effects suggest that restoring NAD+ via CD38 inhibition reactivates sirtuin- and NADPH-dependent redox homeostasis pathways that are suppressed in aged macrophages.
The implications extend beyond oral health. NAD+ depletion is a hallmark of multiple aging-associated conditions including neurodegeneration, type 2 diabetes, and cancer. The finding that a single enzymatic target — CD38 — can be inhibited to simultaneously address inflammation and oxidative stress in aged innate immune cells supports broader interest in CD38 inhibitors as anti-aging therapeutics. For periodontitis specifically, the results suggest a pharmacological strategy that could complement existing treatments by correcting the underlying immunometabolic dysfunction rather than merely suppressing symptoms.
Limitations include the exclusive use of a murine ex vivo model, which may not fully recapitulate human aging biology or the complex polymicrobial oral environment. The study also did not assess in vivo periodontal bone loss outcomes with 78c treatment, nor did it examine longer-term safety or dose optimization. Future work should validate these findings in human macrophages and aged animal models with established periodontitis.
Key Findings
- Old murine macrophages showed 3.1× (Aa) and 2.3× (Pg) higher CD38 protein than young controls 24 h post-infection.
- NAD+ levels were ~43% lower in infected old macrophages versus young controls, correlating with elevated CD38.
- Aged macrophages showed delayed, weaker NF-κB/PI3K/MAPK signaling, meaning high CD38 is age-intrinsic, not immune-activation-driven.
- CD38 inhibitor 78c restored NAD+, reduced IL-1β, IL-6, TNF-α, and cut ROS and Nox1 in infected old macrophages.
- 78c upregulated five antioxidant enzymes (Sod1, Gpx4, Prdx1, Txnrd1, Cat), rebalancing redox homeostasis in aged cells.
Methodology
Young (3-month) and old (18–20-month) murine bone marrow-derived macrophages were infected with Aggregatibacter actinomycetemcomitans or Porphyromonas gingivalis for 1–24 hours. CD38, NAD+, protein kinases (NF-κB, PI3K, MAPKs), cytokines (IL-1β, IL-6, TNF-α), ROS, Nox1, and five antioxidant enzymes were quantified by Western blot, ELISA, and fluorometric assays. Old BMMs were treated with vehicle or the selective CD38 inhibitor 78c prior to infection to assess therapeutic effects.
Study Limitations
The study used only murine ex vivo macrophage models, limiting direct translation to human aging biology and the polymicrobial in vivo oral environment. No in vivo periodontal bone loss endpoints were measured with 78c treatment, leaving functional efficacy in a disease model unconfirmed. Dose optimization, pharmacokinetics, and long-term safety of 78c in aging contexts were not evaluated.
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