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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Nitric oxide induces apoptosis in spleen lymphocytes from MRL/lpr mice
1Medical University of South Carolina, Department of Medicine, Division of Rheumatology, 96 Jonathan Lucas Street, Suite 912, PO Box 250637, Charleston, SC 29425, USA. oatesjc@musc.edu
Background:
MRL/MpJ-Tnfrsf6lpr(MRL/lpr) mice, a murine model of systemic lupus erythematosus (SLE), have defective expression of Fas, substantially reducing signaling for apoptosis via this mechanism. However, it is known that MRL/lpr mice have increased spontaneous apoptosis of leukocytes. These conflicting observations have stimulated interest in apoptosis in this SLE model. MRL/lpr mice overproduce nitric oxide (NO) as autoimmune disease progresses. In vitro administration of NO may induce or decrease apoptosis depending on the cell type. Therefore, we hypothesized that NO induces MRL/lpr spleen lymphocyte apoptosis independent of Fas receptor engagement.
Methods:
Percentages of apoptotic spleen lymphocytes from MRL/lpr and BALB/cJ mice were determined ex vivo after in vivo treatment with NG-monomethyl-L-arginine (NMMA), a nitric oxide synthase (NOS) inhibitor. After culture in varying concentrations of a slow-acting NO donor, the following were determined in spleen lymphocytes: (1) levels of apoptosis, (2) the effect of phorbol myristate acid (PMA) on levels of NO-induced apoptosis, and (3) protein kinase C (PKC) activity.
Results:
Spleen lymphocytes from MRL/lpr mice with active disease had increased levels of ex vivo apoptosis when compared with BALB/cJ controls. This increase was reduced by pharmacologic inhibition of NOS in MRL/lpr but not in BALB/cJ mice. Exogenous administration of NO in vitro reduced PKC activity and induced apoptosis in MRL/lpr spleen lymphocytes, an effect that could be reduced via coadministration of PMA in vitro.
Conclusion:
These results suggest that NO plays a role in spleen lymphocyte apoptosis in MRL/lpr mice, possibly via inhibition of PKC, despite a Fas defect.
Insights
Nitric oxide (NO) induces apoptosis in spleen lymphocytes of MRL/lpr mice, a model for lupus. This occurs independently of the Fas receptor, potentially by inhibiting protein kinase C (PKC).
Area of Science:
- Immunology
- Cell Biology
- Autoimmune Diseases
Background:
- MRL/lpr mice, a model for systemic lupus erythematosus (SLE), exhibit defective Fas expression and increased spontaneous leukocyte apoptosis.
- Nitric oxide (NO) production increases with disease progression in MRL/lpr mice, with known in vitro effects on apoptosis varying by cell type.
Purpose of the Study:
- To investigate the hypothesis that NO induces apoptosis in MRL/lpr spleen lymphocytes independently of Fas receptor engagement.
Main Methods:
- Ex vivo apoptosis levels in spleen lymphocytes from MRL/lpr and BALB/cJ mice were assessed after in vivo treatment with a nitric oxide synthase (NOS) inhibitor (NMMA).
- In vitro studies involved culturing spleen lymphocytes with varying NO donor concentrations to determine apoptosis levels, the impact of phorbol myristate acid (PMA) on NO-induced apoptosis, and protein kinase C (PKC) activity.
Main Results:
- MRL/lpr mice with active disease showed higher ex vivo spleen lymphocyte apoptosis compared to BALB/cJ controls.
- Inhibition of NOS reduced apoptosis in MRL/lpr mice but not BALB/cJ mice.
- In vitro NO administration decreased PKC activity and induced apoptosis in MRL/lpr lymphocytes, an effect mitigated by PMA coadministration.
Conclusions:
- NO plays a significant role in spleen lymphocyte apoptosis in MRL/lpr mice.
- This NO-mediated apoptosis may occur through the inhibition of PKC, despite the known Fas defect in this SLE model.
