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G protein-coupled receptor kinase 6 controls chronicity and severity of dextran sodium sulphate-induced colitis in
Niels Eijkelkamp1, Cobi J Heijnen, Ayscha Lucas
1Laboratory for Psychoneuroimmunology, University Medical Center Utrecht, Lundlaan 6, Room KC 03.063.0, 3584 EA Utrecht, The Netherlands.
Background:
Infiltration of inflammatory cells into the colon plays an important role in the onset and course of inflammatory bowel disease. G-protein-coupled receptor kinase 6 (GRK6) is an intracellular kinase that regulates the sensitivity of certain G-protein-coupled receptors, including those involved in the migration of inflammatory cells. Therefore, it is hypothesised that GRK6 plays a role in determining the course of inflammation.
Aim:
To analyse the role of GRK6 in the course of dextran sodium sulphate (DSS)-induced colitis.
Methods:
Colitis was induced by administering 1% DSS in drinking water to GRK6(-/-), GRK6(+/-) and wild-type (WT) mice for 6 days. The severity of colitis was assessed on the basis of clinical signs, colon length and histology. Moreover, keratinocyte-derived chemokine (KC) levels, granulocyte infiltration, interleukin 1beta (IL1beta), CD4, CD8 and forkhead box protein P3 (FoxP3) expression in the colon were determined. In addition, regulatory T cell function in WT and GRK6(-/-) mice was analysed. The chemotactic response of granulocytes to colon culture supernatants was assessed using a transendothelial migration assay.
Results:
The severity of colitis was increased in GRK6(-/-) and GRK6(+/-) mice and was accompanied by increased KC levels and increased granulocyte infiltration. Moreover, the chemotactic response of GRK6(-/-) granulocytes to supernatants of colon cultures was enhanced. Interestingly, the WT mice completely recovered from colitis, whereas the GRK6(-/-) and GRK6(+/-) mice developed chronic colitis, which was accompanied by increased IL1beta and CD4 expression and decreased FoxP3 expression. Moreover, regulatory T cell function was impaired in the GRK6(-/-) mice.
Conclusions:
The intracellular level of GRK6 is an important factor in determining the onset, severity and chronicity of DSS-induced colitis.
Insights
G-protein-coupled receptor kinase 6 (GRK6) deficiency exacerbates dextran sodium sulphate (DSS)-induced colitis in mice, leading to increased inflammation and impaired regulatory T cell function. GRK6 levels are crucial for managing colitis severity and chronicity.
Area of Science:
- Immunology
- Gastroenterology
Background:
- Inflammatory cell infiltration in the colon is key in inflammatory bowel disease.
- G-protein-coupled receptor kinase 6 (GRK6) regulates G-protein-coupled receptors involved in inflammatory cell migration.
Purpose of the Study:
- To investigate the role of GRK6 in dextran sodium sulphate (DSS)-induced colitis.
Main Methods:
- Administered DSS to GRK6 knockout, heterozygous, and wild-type mice.
- Assessed colitis severity via clinical signs, colon length, and histology.
- Measured inflammatory markers, immune cell infiltration, and regulatory T cell function.
Main Results:
- GRK6 deficiency worsened colitis severity, increasing keratinocyte-derived chemokine (KC) and granulocyte infiltration.
- GRK6 knockout mice showed enhanced granulocyte chemotaxis and developed chronic colitis with altered cytokine expression.
- Impaired regulatory T cell function was observed in GRK6 knockout mice.
Conclusions:
- GRK6 intracellular levels significantly influence the onset, severity, and chronicity of DSS-induced colitis.
- GRK6 plays a critical role in regulating inflammatory responses within the colon.
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