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Gene expression profiling reveals upregulation of Tlr4 receptors in Cckb receptor deficient mice
Sulev Kõks1, Cathy Fernandes, Kaido Kurrikoff
1Department of Physiology, Centre of Molecular and Clinical Medicine, University of Tartu, Tartu 50411, Estonia. Sulev.Koks@ut.ee <Sulev.Koks@ut.ee>
Abstract:
The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control mice. The patterns of gene expression differences suggest that the immune system is activated in higher brain structures following CCI in the wt mice. The strongest differences include genes related to the MAPK pathway activation and cytokine production. In Cckbr KO mice this expressional pattern was absent. In addition, we found significant elevation of the Toll-like receptor 4 (Tlr4) in the supraspinal structures of the mice with deleted Cckbr compared to wt control mice. This up-regulation is most likely induced by the deletion of Cckbr. We suggest that there is a functional deficiency in the Tlr4 pathway which disables the development of neuropathic pain in Cckbr KO mice. Indeed, real time PCR analysis detected a CCI-induced upregulation of Tlr4 and Il1b expression in the lumbar region of wt but not Cckbr KO mice. Gene expression profiling indicates that elements of the immune response are not activated in Cckbr KO mice following CCI. Our findings suggest that there may be a role for CCK in the regulation of innate immunity.
Insights
Mice lacking the cholecystokinin B receptor (Cckbr KO) show protection against neuropathic pain. This is linked to suppressed immune system activation and altered Toll-like receptor 4 (Tlr4) pathways.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Neuropathic pain, induced by chronic constriction injury (CCI), is a debilitating condition.
- The cholecystokinin B receptor (Cckbr) plays a role in pain modulation, but its precise mechanism in neuropathic pain is unclear.
- Previous studies show Cckbr knockout (Cckbr KO) mice are protected against CCI-induced allodynia.
Purpose of the Study:
- To investigate the underlying mechanisms of Cckbr-mediated protection against neuropathic pain.
- To compare gene expression patterns in the midbrain and medulla of Cckbr KO and wild-type (wt) mice following CCI.
- To explore the role of immune pathways and Toll-like receptor 4 (Tlr4) in this protective effect.
Main Methods:
- Gene expression profiling in the midbrain and medulla of Cckbr KO and wt mice after CCI induction.
- Analysis of genes related to immune response, MAPK pathway, and cytokine production.
- Real-time PCR to validate expression levels of Tlr4 and Il1b.
Main Results:
- Wt mice showed activated immune system gene expression, including MAPK pathway and cytokines, after CCI.
- Cckbr KO mice did not exhibit this immune activation pattern following CCI.
- Toll-like receptor 4 (Tlr4) was significantly elevated in Cckbr KO mice, suggesting a functional deficiency in this pathway that prevents neuropathic pain development.
- CCI-induced upregulation of Tlr4 and Il1b was observed in wt mice but not in Cckbr KO mice.
Conclusions:
- The absence of Cckbr prevents the development of neuropathic pain by inhibiting immune system activation in response to CCI.
- A functional deficiency in the Tlr4 pathway in Cckbr KO mice likely contributes to pain protection.
- These findings suggest a potential role for cholecystokinin (CCK) in regulating innate immunity and neuropathic pain.
