Effects Of CD38 Research Articles

CD38: A Significant Regulator of Macrophage Function.

Cluster of differentiation 38 (CD38) is a cell surface glycoprotein and multifunctional extracellular enzyme. As a NADase, CD38 produces adenosine through the adenosine energy pathway to cause immunosuppression. As a cell surface receptor, CD38 is necessary for immune cell activation and proliferation. The aggregation and polarization of macrophages are affected by the knockout of CD38. Intracellular NAD+ levels are reduced by nuclear receptor liver X receptor-alpha (LXR) agonists in a CD38-dependent manner, thereby reducing the infection of macrophages. Previous studies suggested that CD38 plays an important role in the regulation of macrophage function. Therefore, as a new marker of macrophages, the effect of CD38 on macrophage proliferation, polarization and function; its possible mechanism; the relationship between the expression level of CD38 on macrophage surfaces and disease diagnosis, treatment, etc; and the role of targeting CD38 in macrophage-related diseases are reviewed in this paper to provide a theoretical basis for a comprehensive understanding of the relationship between CD38 and macrophages.

Abstract 296: Cd38 Deficiency Protects Heart From Lipid Overload-induced Oxidative Stress via Activating Sirt3/foxo3 Pathway

Background/Aims: Our and other studies showed that CD38 deficiency protected heart from ischemia/reperfusion injury and high fat diet (HFD)-induced obesity in mice, respectively. However, the roles of CD38 in lipid overload-induced heart injury were not evaluated. In the present study, we investigated the preventive effects and mechanisms of CD38 deficiency on mouse heart injury induced by HFD. Methods: The discrepant metabolites in heart from wild type (WT) and CD38 knockout (CD38 -/- ) mice fed with HFD were examined using metabolomics analysis. The cell viability, the lactate hydrogenase (LDH) release, super oxide dismutase (SOD) activity, reactive oxygen species (ROS) production, triglyceride concentration and the expressions of various corresponding genes were examined for evaluating the effects of CD38 on oleic acid (OA)-induced cell injury using CD38 knockdown H9C2 stable cell line. Results: Our results revealed that CD38 deficiency significantly elevated the intracellular glutathione (GSH) concentration and GSH/GSSG ratio, decreased the contents of various free fatty acids and increased intracellular NAD + level in heart of CD38 -/- mice fed with HFD. Knockdown of CD38 significantly attenuated OA-induced cell injury, ROS production and lipid synthesis, seen as enhancing cell viability, reducing LDH release, elevating SOD activity, and decreasing triglyceride content and expressions of FASN in the CD38 knockdown H9C2 stable cell line. In addition, we also observed that the mitochondrial deacetylase Sirt3 and its target genes FOXO3 and SOD2 were upregulated in the stable cell lines after OA stimulation. Furthermore, the expressions of NOX2 and NOX4 were attenuated, accompanied by decreasing Bax expression and increasing Bcl-2 expression in the cells after OA stimulation. Conclusions: Our results demonstrated that CD38 deficiency protected heart from HFD-induced oxidative stress via activating Sirt3/FOXO3-mediated anti-oxidative stress pathway.

CD38 Facilitates Recovery from Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It causes progressive tissue atrophy and consequent neurological dysfunctions. TBI is accompanied by neuroinflammation, a process mediated largely by microglia. CD38 is an ectoenzyme that promotes transmembrane signaling via the synthesis of potent calcium mobilizing agents or via its receptor activity. CD38 is expressed in the brain in various cell types including microglia. In previous studies, we showed that CD38 regulates microglial activation and response to chemokines. In view of the important role of neuroinflammation in TBI and the effects of CD38 on microglial responses, the present study examines the role of CD38 in the recovery of mice from closed head injury (CHI), a model of focal TBI. For this purpose, CD38-deficient and wild-type (WT) mice were subjected to a similar severity of CHI and the effect of the injury on neurobehavioral and cognitive functions was assessed by the Neurological Severity Score (NSS) and the Object Recognition Test, at various time points post-injury. The results show that recovery after CHI (as indicated by the NSS) was significantly lower in CD38-deficient mice than in WT mice and that the object recognition performance after injury was significantly impaired in injured CD38-deficient mice than in WT mice. In addition, we also observed that the amount of activated microglia/macrophages at the injury site was significantly lower in CD38-deficient mice compared with WT mice. Taken together, our findings indicate that CD38 plays a beneficial role in the recovery of mice from CHI and that this effect is mediated, at least in part, via the effect of CD38 on microglia responses.

Evaluation of the antiretroviral effects of a PEG-conjugated peptide derived from human CD38

Objective: Cell infection by HIV-1 is inhibited by both the expression of CD38 and a soluble peptide (sCD38p) corresponding to its extracellular membrane-proximal amino acid sequence (amino acids 51 – 74). We show here the effects of PEG conjugation to sCD38p and provide new insights into the mechanisms behind the anti-HIV-1 effects of CD38 and derived peptides. Research design/methods: In-vitro and in-silico study. Results: PEGylation of sCD38p increased its ability to inhibit replication of HIV-1 in MT-4 cells and syncytia formation in cocultures of MT-2 and persistently HIV-1IIIB-infected H9IIIB cells. In silico modeling suggests that sCD38p and CD4 form stable heterodimers involving, among others, an interaction between lysine 57 (K57) of CD38 and a groove in the CD4 receptor, which, in CD4/gp120 complexes, is partially occupied by a lysine residue of the HIV-1 envelope glycoprotein. K57 substitution with a glycine in sCD38p impaired its ability to inhibit syncytia formation in MT-2/H9IIIB cell cocultures and gp120 binding to CD4 in a mouse T cell line expressing human but not mouse CD4. Conclusions: PEGylation significantly improves the anti-HIV-1 activity of sCD38p, whose effect is probably due to competition with gp120 for a common binding site on CD4 although other mechanisms cannot be excluded so far. The inhibitory concentrations of the sCD38p-PEG as well as its poor toxicity, merit further consideration in anti-HIV-1 strategies.

Cellular Expression of CD23, CD71, and CD38 Are Independent Prognostic Variables in B-Cell Chronic Lymphocytic Leukemia.

Prognostic factors available to help predict the outcome of patients with B-cell chronic lymphocytic leukemia (B-CLL) include clinical stage, lymphocyte doubling time, cytogenetic abnormalities, immunoglobulin heavy chain variable region (IgVH) mutation status, serum factors such as soluble CD23 and, in particular, cellular phenotyping. For instance, several studies have shown that cellular expression of CD38 or zap-70, as assessed by flow cytometry, is associated with a more aggressive course of disease. However, previous phenotyping studies have not addressed the significance of more subtle findings such as whether bimodal expression (the identification of two discrete cell populations within the neoplasm) or the level of antigen expression impacts patient outcome. Therefore, a retrospective analysis of flow cytometry data from 246 patients diagnosed with B-CLL at University Hospitals of Cleveland and Case Western Reserve University was performed. Twenty-five different antigens were assessed for bimodality and the level of expression of all antigens was determined on a 0–3 scale. CD38 and CD71 expression level was further analyzed as percent positive over control. The optimal threshold values of CD38 and CD71 was estimated by the tree-structure survival method. Bimodality was identified by visual inspection of the flow cytometry histograms. The overall survival was measured from the date of analysis to date of death and censored at the date of last follow-up for survivors. Survival distribution was estimated using Kaplan-Meier methods and difference between/among groups was examined using log rank test. The mean follow-up was an average of 2.7 years. Bimodal antigen expression was found in 107 (43%) of all analyzed cases. However, neither the presence of bimodality by itself, nor the number of bimodal antigens per case was associated with worse overall survival. Bimodality of CD38, identified in 14.5% of cases, was not correlated with a worse overall survival in this study and bimodality of individual antigens CD13 (12.9%), CD11c (7.9%), CD20 (7.3%), CD5 (7.3%), FMC-7 (6.4%), and surface immunoglobulin (4.5%) also did not impact survival. Antigens bimodal in less than 4.5% of cases were not analyzed. In multivariate analysis, the expression level of CD38, CD23 and CD71 were found to be independent prognostic risk factors. The effect of CD38, CD23, and CD71 on overall survival, controlling for the effect of age, was further estimated using the Cox proportional hazards model. The relative risk of dying for patients with CD71 expression on B-CLL cells less than 9.5% was 6.37 (p = 0.0001, CI 2.56–15.87) compared to patients expressing higher levels of CD71. Patients with low level B-CLL cellular CD23 expression had a relative risk of dying of 4.22 (p= 0.007, CI 1.49–11.9) compared to those patients expressing higher levels of CD23 and those patients with B-CLL cells expressing CD38 greater than 24.5% had a relative risk of dying of 2.85 (p = 0.016, CI 1.22 – 6.65) compared to those patients expressing lower levels of CD38. Taken together, our findings show for the first time that cellular expression of CD23 and CD71 impact survival in B-CLL and indicate that the level of expression of CD38, CD23, and CD71 are independent risk factors while bimodal antigen expression appears not to influence outcome in B-CLL patients.