Background/Purpose:

Colony-stimulating factors (CSF) are simply defined as haemotopoitec growth factors. However, CSFs have been implicated to have additional functions in various autoimmune diseases. Specifically M-CSF has been shown to effect the progression of CIA, a murine model of RA. Additional studies have also shown that M-CSF is required to maintain the monocyte derived macrophage population in the ankle. However, all of these studies utilized M-CSF or MCSFR knockout or mutant mice.  Here we generated MCSFR conditional mice that lack the receptor in myeloid cells. We hypothesize that M-CSF is integral to the development of monocytes and subsequent macrophage differentiation, and will affect the development of other autoimmune diseases.

Methods:

We generated mice lacking M-CSF-R specifically in myeloid cells (M-CSF-R^fl/flCre^LysM) and assessed mice at 4 months of age for characterization of RA-like disease.  Monocyte turnover/proliferation and differentiation were examined in vivousing flow cytometric analyses.

Results:

M-CSF-R^fl/flCre^LysM displayed a normal response and recovery to RA in our K/BxN serum transfer arthritis (STIA) model. However flow cytometry analysis revealed differential cell populations in multiple tissues within M-CSF-R^fl/flCre^LysM mice compared to M-CSF-R^fl/fl mice. We observed a marked decreased in the non-classical monocytes in which the M-CSF-R^fl/fl was deleted.  Since blood monocytes are directly linked to the formation of tissue inflammatory macrophages we also examined synovial macrophages in the ankle.  We previously characterized synovial macrophages as MHCII^–, tissue resident macrophages, and MHCII⁺ macrophages. M-CSF-R^fl/flCre^LysM mice showed a significant decrease in MHCII⁺macrophages.

Conclusion:

M-CSF plays a central role in both monocyte differentiation in the blood and MHCII⁺ macrophage proliferation in the ankle. The lack of M-CSF-R depletion in both intermediate and non-classical monocytes, in the blood, suggests that expression of M-CSF-R is required for classical monocytes to differentiate into non-classical monocytes. This data also suggest that M-CSF can act as either an active or passive participant in the replenishment of synovial macrophages. M-CSF could be directly required for the differentiation of monocytes into synovial macrophages. The decrease in MHCII⁺ cells could also be due to the decreased ability of classical monocytes to differentiate into non-classical monocytes, suggesting that non-classical monocytes directly replenish the synovial macrophage populations. The M-CSF-R^fl/flCre^LysM provides an important model to study autoimmune disease and identify the specific role of M-CSF in classical and non-classical monocyte differentiation and their ability to replenish both tissue resident and bone marrow derived macrophages during the progression of disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/m-csf-r-is-a-critical-determinant-for-the-differentiation-of-classical-to-non-classical-monocytes/