Wednesday, 23 July 2014

What macrophage does what?

Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, Wu PM, Doykan CE, Lin J, Cotleur AC, Kidd G, Zorlu MM, Sun N, Hu W, Liu L, Lee JC, Taylor SE, Uehlein L, Dixon D, Gu J, Floruta CM, Zhu M, Charo IF, Weiner HL, Ransohoff RM. Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med. 2014 Jul. pii: jem.20132477. [Epub ahead of print]

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. We show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.
In this study they suggest that blood-derived macrophages that enter the CNS are the cells causing the damage whereas the brain derived macrophages called microglia do the mopping up and clear the debris after this destruction and may promote the repair process.
Targeting the macrophage arm of the immune response can be just as effective as targeting T cell responses, the question is what would the side-effect profile be like?

5 comments:

  1. So much for the "hot microglia" theory.

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    1. Not really. This study focuses on the acute phase of disease in mice but does not study what happens to the microglia over a long period of time. The presence of large numbers of activated microglia around old lesions may well be contributing to progression. The same thing is implicated in the development of Alzheimers.

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  2. In context of MS pathology, do you feel this innate immune activity precedes T-cell activation of microglia at the outset of disease or is this solely a consequence of chronic activity? Clinically, does this support Natalizumab effectiveness in targeting innate and adaptive immune activity in relapsing and progressive MS?

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    1. If you look at pre-active lesions there is innate immune activation away from lymphoid cells however do they have to be nearby...the answer may be "no" as their soluble factors may travel some distance from the cell. Likewise as soon as T cells arrive the innate immune activation will occur because of gamma interferon, however chronic and acute lesions are probably not the same. Natilizumab will target both as macrophages and T and B cells etc both express the target

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  3. It MS, P2X7R receptors are activated which is a notifier that the cell should be destroyed which activates the innate immune system (macrophages or microglia). The P2X7R receptors are activated via. extracellular ATP which can be released through cell injury.

    So, it seems the people who are going down the "virtual hypoxia" path seem to have a clue as to what is going on in MS.

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