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Zoledronic acid mediated differential activation of NK cells in different organs of WT and Rag2-/- mice; stark
Kawaljit Kaur1, Keiichi Kanayama2, Qing-Qing Wu3
1Division of Oral Biology and Medicine, University of California School of Dentistry, 10833 Le Conte Ave, 90095 Los Angeles, USA; Weintraub Center for Reconstructive Biotechnology, UCLA School of Dentistry, Los Angeles, CA USA 90095.
Abstract:
We have previously shown that natural killer (NK) cells expand, and increase their function after interaction with cells that exhibit a number of different knock-down genes. We hypothesized that deletion or knockdown of a variety of key genes such as RAG may cause de-differentiation of the cells which could lead to increased NK expansion and function since we have shown previously that NK cells are activated and expanded by less differentiated cells. When comparing the function of NK cells from bone marrow (BM), spleen, pancreas, adipose tissue, and gingiva from WT mice to those from Rag2-/- mice, we observed a significant increase in IFN-γ secretion in all tissues of Rag2-/- mice versus in WT mice, with the exception of the gingivae in which similar levels were observed. After injecting WT mice with zoledronic acid (ZOL) and tooth extraction, immune cells from BM, spleen, and purified NK cells from spleen exhibited very high induction of IFN-γ and NK cell-mediated cytotoxicity with the exception of gingiva in which immune cells exhibited the opposite. In Rag2-/- mice, ZOL injection and tooth extraction stimulated IFN-γ secretion from BM immune cells but inhibited IFN-γ secretion from both spleen and gingivae. In both WT and Rag2-/- mice, immune cells from gingivae exhibited decreased IFN-γ secretion when activated, indicating significant regulation of immune cell function in the gingival microenvironment. However, even though significantly lower induction of IFN-γ was observed in both WT and Rag2-/- gingival cells after ZOL injection, ZOL mediated secretion of IFN-γ was still higher in the gingivae of WT mice when compared to those of Rag2-/- gingival cells. These results suggest an important role for IFN-γ in the pathogenesis of osteonecrosis lesions observed in post-tooth extraction jawbone.
Insights
Deletion of key genes like RAG may enhance natural killer (NK) cell function. Zoledronic acid (ZOL) and tooth extraction impact immune responses, particularly in the jawbone, suggesting a role for IFN-γ in osteonecrosis.
Area of Science:
- Immunology
- Cell Biology
- Genetics
Background:
- Natural killer (NK) cells are crucial immune cells known to expand and enhance function upon interaction with cells exhibiting gene knockdowns.
- Previous research suggests that NK cells are activated and expanded by less differentiated cells.
Purpose of the Study:
- To investigate the hypothesis that deleting key genes, such as RAG, may lead to cell de-differentiation, consequently increasing NK cell expansion and function.
- To compare NK cell function in various tissues of wild-type (WT) and Rag2 knockout (Rag2-/-) mice.
- To examine the effects of zoledronic acid (ZOL) and tooth extraction on immune cell function, particularly interferon-gamma (IFN-γ) secretion and NK cell-mediated cytotoxicity, in different tissue microenvironments.
Main Methods:
- Comparative analysis of immune cell function (IFN-γ secretion, NK cell-mediated cytotoxicity) in bone marrow (BM), spleen, pancreas, adipose tissue, and gingiva from WT and Rag2-/- mice.
- Administration of ZOL and tooth extraction in WT and Rag2-/- mice, followed by assessment of immune cell responses in various tissues.
- Evaluation of immune cell function specifically within the gingival microenvironment.
Main Results:
- Rag2-/- mice showed significantly increased IFN-γ secretion in most tissues compared to WT mice, except for the gingiva.
- In WT mice, ZOL and tooth extraction induced high IFN-γ and NK cell activity in BM and spleen, but suppressed it in the gingiva.
- In Rag2-/- mice, ZOL and tooth extraction stimulated IFN-γ in BM but inhibited it in spleen and gingiva, with gingival immune cells showing decreased IFN-γ secretion in both genotypes upon activation.
Conclusions:
- Gingival immune cell function is significantly regulated within its microenvironment, showing decreased IFN-γ secretion upon activation in both WT and Rag2-/- mice.
- Despite lower induction, ZOL-mediated IFN-γ secretion was higher in WT gingival cells compared to Rag2-/- gingival cells.
- These findings highlight a critical role for IFN-γ in the pathogenesis of osteonecrosis lesions observed in jawbone post-tooth extraction.
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