CD38 Deficiency Downregulates the Onset and Pathogenesis of Collagen-Induced Arthritis through the NF-κB Pathway

Abstract

Aim. The RelB gene plays an important role in guiding the progression of arthritis. We have previously demonstrated that the expression of the RelB gene is decreased significantly in bone marrow DCs of CD38-/- mice. In this study, we demonstrate that the cluster of the differentiation (CD38) gene could be a potentially therapeutic target for autoimmune arthritis. Method. Collagen-induced arthritis (CIA) models were generated with both the wild-type (WT) C57BL/6 and CD38-/- mice. The expression of the RelB gene and maturation of bone marrow-derived dendritic cells (DCs) from the WT and CD38-/- mice were detected. Antigen-specific T cell responses, joint damage, and expression of proinflammatory cytokines were assessed. The effects of the Nuclear Factor Kappa B (NF-κB) transcription factor and its mechanisms were characterized. Results. We demonstrated that in CD38-/- mice, the expression of the RelB gene and major histocompatibility complex II (MHC II) was decreased, accompanied with the inhibited T cell reaction in a mixed lymphocyte reaction (MLR) in bone marrow-derived DCs. Compared to the serious degeneration of the cartilage and the enlarged gap of the cavum articular in WT CIA mice, joint pathological changes of the CD38-/- CIA mice revealed marked attenuation, while the joint structures were well preserved. The preserved effects were observed by the inhibition of proinflammatory cytokines and promotion of anti-inflammatory cytokines. Furthermore, decreased phosphorylation of NF-κB was also observed in CD38-/- CIA mice. Conclusion. We demonstrate that CD38 could regulate CIA through NF-κB and this regulatory molecule could be a novel target for the treatment of autoimmune inflammatory joint disease.

The new insight into extracellular NAD+ degradation‐the contribution of CD38 and CD73 in calcific aortic valve disease

“…Investigating the mechanisms that can be observed in the CAVD development process requires further research. There is some evidence to suggest that CD38 has been shown to regulate chronic inflammatory diseases such as autoimmune arthritis via nuclear factor kappa‐B pathway (NF‐κB), and this regulatory molecule may be a new target in the treatment of autoimmune inflammation 59 . Moreover, the activation of the canonical NF‐κB pathway is responsible for the selective regulation of pro‐inflammatory and thrombotic reactions in human atherosclerosis 60 .…”

Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD

“…Therefore, it is of little surprise that NF-κB can activate CD38 [161], though recent evidence suggests CD38 may further amplify NF-κB signaling. CD38 KO mice were found to have greatly diminished NF-κB signaling in an autoimmune arthritic mouse model [162]. Further, inhibition of CD38 by the senolytic flavonoid quercetin was shown to reduce NF-κB signaling and M1 macrophage polarization in kidney and spleen tissue following IP LPS administration [154].…”

The Good, the Bad and the Unknown of CD38 in the Metabolic Microenvironment and Immune Cell Functionality of Solid Tumors

“…There was a lack of induction of invariant NKT (iNKT) cells in the spleen of CD38 KO mice, as well as reduced percentages of Th1 cells in the draining lymph nodes. CD38-null bone marrow-derived dendritic cells (BMDCs) have a decreased expression of RelB, which is an important regulator of CIA, as well as a decreased MHCII expression and repressed antigen presentation [20]. CIA mice display aberrant joint structures, whereas CD38 −/− CIA mice have a dramatic attenuation of joint pathology, likely through the attenuation of NF-κB signaling and a decrease in proinflammatory cytokines such as IL-1β.…”

“…CD38 has been extensively studied for its role in hematological malignancies, including chronic lymphocytic leukemia [16,17] and multiple myeloma [17][18][19]. Research on CD38 and its involvement in chronic inflammatory diseases, such as rheumatoid arthritis [20,21] and asthma [22,23], indicates that the aberrant expression and hyperactivity of CD38 can tip immune responses towards disease pathology. The understanding of how this immune cell marker may influence the progression and immune evasion within solid tumors is a relatively new field.…”