Saturday, October 24, 2015

Specialized monocyte subset protects lung vasculature from tumor metastases

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 Nur77hematopoietic 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-CreNr4a1fl/fl and LysM-CreNr4a1fl/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

5 comments:

  1. I have not read this article yet but is on my must to do list.
    Just a question:
    How they confirm that these cells are monocytes and specialized? And why not macrophages?

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  2. They say Nr4a1 is expressed at high level only on these monocytes. Apparently, macrophages and Ly6Chigh monocytes express it at low level.

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    1. These 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.

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  3. Hi Jaba

    That'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

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    1. I did not look who the authors are. Again Hanna et al. :)
      Now I know why are they 'for monocytes'.

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