CD38 activation by monosodium urate crystals contributes to inflammatory responses in human and murine macrophages.

Cluster of differentiation (CD) 38, a major enzyme for nicotinamide adenine dinucleotide (NAD+) degradation, plays a key role in inflammation. Meanwhile, intracellular NAD+ decline is also associated with inflammatory responses. However, whether CD38 activation is involved in gouty inflammation has not been elucidated. The present study aimed to clarify the role of CD38 in monosodium urate crystals (MSU)-triggered inflammatory responses. The results showed that MSU crystals increased the protein expression of CD38 in time- and concentration-dependent manner in THP-1 macrophages and mouse bone marrow-derived macrophages (BMDMs). Moreover, intracellular NAD+ levels were reduced by MSU crystals along with the increased IL-1ß release. However, CD38 inhibition by 78c elevated intracellular NAD+ levels and suppressed IL-1ß release in MSU crystals-treated THP-1 macrophages and BMDMs. Interestingly, CD38 inhibition without significant elevation of intracellular NAD+ also decreased IL-1ß release driven by MSU crystals in THP-1 macrophages. In conclusion, the present study revealed that MSU crystals could activate CD38 with the ensuing intracellular NAD+ decline to promote inflammatory responses in THP-1 macrophages and BMDMs, while CD38 inhibition could suppress MSU crystals-triggered inflammatory responses, indicating that CD38 is a potential therapeutic target for gout.

Transient receptor potential melastatin-2 and temperature participate in the process of CD38-regulated oxytocin secretion.

In recent studies, oxytocin showed potential for the treatment of mental diseases. CD38 is essential for oxytocin release, and hence plays a critical role in social behavior. CD38 catalyzes ß-NAD into cyclic ADP ribose (cADPR), which could elevate the intracellular Ca by Ca-permeable channels for oxytocin secretion. The temperature-sensitive cation channel, transient receptor potential melastatin-2 (TRPM2), is a cation-nonselective cation and has been shown to affect oxytocin indirectly. The aim of the present study was to verify the participation of temperature and TRPM2 in CD38-regulated oxytocin release. The crude membranes were prepared to isolate the nerve terminals from the posterior pituitary. At 34°C, 37°C, and 39°C, agonists (ß-NAD, ADPR, cADPR) and antagonists (8-Br-cADPR, 2-APB) were used to stimulate the nerve terminals. Oxytocin releases were investigated by enzyme-linked immunosorbent assay. In addition, the expression of TRPM2 and CD38 in the hypothalamus and pituitary was detected by western blotting and quantitative PCR. CD38 agonists (ß-NAD, cADPR) and antagonist (8-Br-cADPR) could increase or reduce the oxytocin release, respectively. TRPM2 agonist (ADPR) and antagonist (2-APB) alone could also regulate oxytocin release. Furthermore, temperature could increase agonist stimulation and attenuate the antagonist inhibition on oxytocin release. In addition, CD38 and TRPM2 were expressed in the hypothalamus and pituitary at both the mRNA and the protein level. TRPM2 in pituitary nerve terminals plays a role in oxytocin release. Temperature- enhanced oxytocin release by CD38 and TRPM2. TRPM2 might be involved in the process of CD38-regulated oxytocin release.

CD38 identifies a hypo-proliferative IL-13-secreting CD4+ T-cell subset that does not fit into existing naive and memory phenotype paradigms.

CD38 is commonly regarded as an activation marker for human T cells. Herein, we show that CD38 expression identifies a hypo-proliferative CD4(+) T-cell subset that, following TCR stimulation, retains expression of naive cell surface markers including CD45RA, CD62L and CCR7. Hypo-proliferation was mediated by reduced CD25 up-regulation upon TCR stimulation compared to CD4(+) CD38(-) cells and lack of responsiveness to exogenous IL-2. Instead, CD4(+) CD38(+) T cells expressed CD127, and hypo-proliferation was reversed by addition of IL-7, further associated with increased STAT5 phosphorylation. This phenotype was exacerbated by addition of an agonistic CD38-binding antibody, suggesting that signaling through CD38 promotes this cell profile. Activated CD4(+) CD38(+) cells had a bias towards IL-13 secretion, but not other Th2 cytokines such as IL-4 or IL-5. In comparison, the CD4(+) CD38(-) cells had a clear bias towards secretion of Th1-associated cytokines IFN-γ and TNF. The existence of such CD4(+) CD38(+) T cells may play an important role in pathologies such as asthma, which are associated with IL-13, but not IL-4 and IL-5. Coupled with responsiveness to IL-7 but not IL-2, and the involvement of CD38 ligation, our results highlight a unique T-cell subpopulation that does not fit into existing naive and memory cell paradigms.