Immune system's cellular lineage diversity is expanding and quite rapidly. Now we have several types of T cells, several types of NK cells, whole new family of innate lymphoid cells (ILCs), cytokine-secreting B cells, specialized subset of neutrophils using sticky DNA nets to trap the microbes.
Here comes a paper in Science showing a new subset of orphan nuclear receptor Nur77-positive monocytes specializing in protection of lung vasculature from tumor metastases.
First, using reporter mice that tracks Nur77+monocytes (encoded by Nr4a1, a Nr4a1-GFP green mice), the authors showed that after intravenous injection of red fluorescent Lewis Lung Carcinoma cells (LLC-RFP), Nur77+monocytes are rapidly accumulating in the lung vasculature, then slowing down their speed in close proximity to tumor cells.
To confirm that Nur77+monocytes play a role in tumor defense, the authors first repeated the same experiment with total Nr4a1-KO mice, which according to the authors, selectively lack Nur77+monocytes. Nra1-KO mice appeared to harbor more lung metastasis (but not in liver), even if tumor cells [B16 melanoma] were injected subQ.
Similarly, increased tumor metastases (but not primary tumors) were seen with mouse model of spontaneous mammary tumor, MMTV-PyMT, receiving Nr4a1-KO bone marrow transfer, supporting the role of Nur77+ hematopoietic cells in prevention of tumor metastases.
To more specifically address the role of Nur77+monocytes in tumor protection, the authors have used two different myeloid-specific Nr4a1 conditional knockout models, CSF1R-Cre+ Nr4a1fl/fl and LysM-Cre+ Nr4a1fl/fl. In both models, there was an increase in tumor metastases to the lung. Interestingly, T cell-specific Nur77 deletion showed no effect on tumor metastases.
Finally, the authors found that receptor CX3CR1 could play an important role in tumor recognition by Nur77+monocytes.
In summary, this study suggest that there is a specialized monocytes lineage defined by Nr4a1 expression that specifically patrol and protects the lung vasculature against tumor metastases.
David Usharauli
First, using reporter mice that tracks Nur77+monocytes (encoded by Nr4a1, a Nr4a1-GFP green mice), the authors showed that after intravenous injection of red fluorescent Lewis Lung Carcinoma cells (LLC-RFP), Nur77+monocytes are rapidly accumulating in the lung vasculature, then slowing down their speed in close proximity to tumor cells.
To confirm that Nur77+monocytes play a role in tumor defense, the authors first repeated the same experiment with total Nr4a1-KO mice, which according to the authors, selectively lack Nur77+monocytes. Nra1-KO mice appeared to harbor more lung metastasis (but not in liver), even if tumor cells [B16 melanoma] were injected subQ.
Similarly, increased tumor metastases (but not primary tumors) were seen with mouse model of spontaneous mammary tumor, MMTV-PyMT, receiving Nr4a1-KO bone marrow transfer, supporting the role of Nur77+ hematopoietic cells in prevention of tumor metastases.
Finally, the authors found that receptor CX3CR1 could play an important role in tumor recognition by Nur77+monocytes.
In summary, this study suggest that there is a specialized monocytes lineage defined by Nr4a1 expression that specifically patrol and protects the lung vasculature against tumor metastases.
David Usharauli
They say Nr4a1 is expressed at high level only on these monocytes. Apparently, macrophages and Ly6Chigh monocytes express it at low level.
ReplyDeleteThese are not a new subset of myeloid cells but patrolling monocytes. In addition, there was a paper from swirski's group (if I am not messing something up) telling macrophages are also NR4A1 Positive and involved in atherosclerosis.
DeleteHi Jaba
ReplyDeleteThat's right. Still, it is kind of new subset, if time of initial discovery is concerned, I think. I did not know that such population existed before I came across this paper :)
Regarding macrophages, you right, the authors mentioned that macrophages too express it but at low level so they think depletion of Nr4a1-positive macrophages may not play as significant role as these patrolling monocytes. But who knows.
David
I did not look who the authors are. Again Hanna et al. :)
DeleteNow I know why are they 'for monocytes'.