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The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline
Claudia Chini, Kelly A. Hogan, Gina M. Warner, Mariana G. Tarragó, Thais R.Peclat, Tamar Tchkoni, James L.Kirkland, Eduardo Chini
https://doi.org/10.1...brc.2019.03.199
Here we investigated if the cellular senescence phenotype is involved in the regulation of CD38 expression and its NADase activity. We observed that senescent cells do not have high expression of CD38. ...
Next, we investigated whether components of the SASP were able to regulate the expression of CD38 in non-senescent cells. M1 macrophages are the prototype CD38-expressing cells, and it has been demonstrated that induction of the M1 phenotype by LPS, TNF-α, and activators of the LXR receptor leads to increased CD38 expression in these cells. In fact, CD38 is proposed to be one of the main markers of induction of the M1 phenotype in macrophages. Here we show that representative SASP factors (TNFα, IL-6, CXCL1, CXCL2) had small or no significant effects on CD38 activity or protein expression when given individually, but when combined promoted a synergistic effect that led to a strong increase in CD38 activity (Fig. 2B) and CD38 protein levels (Fig. 2C) in murine bone marrow-derived macrophages (BMDM).
3.3. Conditioned media from senescent cells induces CD38 expression in macrophages and endothelial cells.
We next tested whether or not conditioned media derived from senescent cells could induce CD38 expression in both inflammatory (BMDM) and non-inflammatory (HUVEC) cells (scheme Fig. 3A). We focused on BMDM and HUVECs because previous reports demonstrate that CD38 in vivo is preferentially expressed in inflammatory and endothelial cells [9,33]. In support of our hypothesis, we observed that exposure to conditioned media from x-ray- or [gamma-radiation]-induced senescent HUVECs leads to increases in CD38 mRNA expression and NADase activity in mouse BMDMs compared to control condioned media (Fig. 3B). [This was later confirmed at the protein level -MR].
It has been previously demonstrated that pre-adipocytes are one of the main cells that become senescent in vivo. ... In support of our hypothesis we observed that conditioned media from senescent preadipocytes derived from two independent [middle-aged obese patients undergoing kidney transplant or gastric bypass surgery] induced CD38 expression and CD38 NADase activity in BMDM, although media from one of the patients caused a much stronger induction of CD38 than the other (Fig. 3C and D). We also observed that the SASP from senescent cells also induced CD38 expression in endothelial cells [again, later confirmed at the protein level, and via] expression of other cellular markers of the M1 phenotype such as IL-6, IL-8, and iNOS. ...
Furthermore, it has also been observed that clearance of senescent cells in vivo can decrease the expression of several components of the SASP including TNF-α, IFNγ, IL-1b, IL-8 and IL-6. This may indicate that senescent cells in vivo may modulate CD38 expression via changes in tissue cytokines and chemokines (Fig. 4C). This hypothesis will be further tested in our laboratory using senolytic agents.
