The Good, The Bad and the Beautiful

Macrophages can be the Good guys  (Phagocytes are molecularly adapted for clearance of tissue debris and the support of CNS repair often termed M2 phagocytes) and also the bad guys (phagocytes with a proinflammatory polarization = classically activated or [M1 phagocytes] release high levels of
toxic mediators, including reactive species, and contribute to CNS
damage). But what makes these differences. In this beautiful study we find that it is environment within the CNS that dictates the path they choose.

Locatelli G, Theodorou D, Kendirli A, Jordão MJC, Staszewski O, Phulphagar K, Cantuti-Castelvetri L, Dagkalis A, Bessis A, Simons M, Meissner F, Prinz M, Kerschensteiner M.Mononuclear phagocytes locally specify and adapt their phenotype in a multiple sclerosis model. Nat Neurosci. 2018;21(9):1196-1208. 

Mononuclear phagocytes are key regulators of both tissue damage and repair in neuroinflammatory conditions such as multiple sclerosis. To examine divergent phagocyte phenotypes in the inflamed CNS, we introduce an in vivo imaging approach that allows us to temporally and spatially resolve the evolution of phagocyte polarization in a murine model of multiple sclerosis. We show that the initial proinflammatory polarization of phagocytes is established after spinal cord entry and critically depends on the compartment they enter. Guided by signals from the CNS environment, individual phagocytes then switch their phenotype as lesions move from expansion to resolution. Our study thus provides a real-time analysis of the temporospatial determinants and regulatory principles of phagocyte specification in the inflamed CNS

In this study they established a phenotype imaging approach based on reporter mice that translate the pro- or anti-inflammatory polarization of phagocytes (M1 or M2) into distinct fluorescent signals.

Imaging of these in real time in an animal model of MS then allowed them to follow the evolution of individual phagocyte types in different CNS compartments during the formation and resolution of inflammatory lesions.

There results show that both lesion stage and CNS compartment influenced the phagocyte polarization in neuroinflammatory lesions.

Phagocytes that enter from the blood stream acquire their initial polarization only after spinal cord entry, and the nature of this polarization critically depends on the compartment they enter. 

While phagocytes in the spinal cord parenchyma predominantly show an M1 polarization at the initial stages of lesion formation, phagocytes in the meninges often display an M2 phenotype. 

Once in the CNS the M1 began a conversion to M2 rather than a new wave of infiltration of M2 cells. This was facilitated by the action of astrocytes.  Phagocytes acquired their initial polarization after CNS entry, and, as the disease evolved, individual phagocytes locally switched their phenotype by passing through a transitional state. Therefore, suggesting that the natural effect of the CNS environment is to turn the bad guys into the good guys. This was associated with changes in biochemical function other than those associated with cytokine production. The critical instructive role of the CNS environment was further emphasized by cell transfers.

Therefore treatments aimied at switching M1 to M2 macrophages may not be needed, as it will happen anyway

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