Endo F, Komine O, Fujimori-Tonou N, Katsuno M, Jin S, Watanabe S, Sobue G, Dezawa M, Wyss-Coray T, Yamanaka K. Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Rep. 2015 Apr 28;11(4):592-604. Epub 2015 Apr 16 PubMed.
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Michigan State University
I think the observations that increasing TGFβ shortens lifespan and blocking TGFβ increases lifespan (assuming the drug does what it is intended to do) are important. ALS has no effective treatments. The paper reinforces the idea that microglial activation can have both beneficial and detrimental influences on neurodegeneration. Not only is the "state/phenotype" of activation critical, so is the magnitude of activation. The T cell infiltration component is intriguing.
Weizmann Institute of Science
It is becoming widely accepted that CNS-infiltrating immune cells play a key role in fighting neurodegenerative conditions. Nevertheless, in most chronic neurodegenerative diseases, the recruitment of these cells into the CNS seems to be insufficient or delayed, resulting in a neuroinflammatory response that contributes to the exacerbation of the pathology. Thus, the neuroinflammation in neurodegenerative diseases has a negative reputation. In this study by Endo and colleagues, the authors examined the involvement of astrocyte-produced TGF-β1 on ALS disease progression in the mSOD1 (G93A) mouse model. TGF-β1 is one of the key cytokines that maintains the “immune-privileged” status of the CNS, and as the authors show, it has a direct immunosuppressive effect on microglia. In addition, they show an indirect effect on microglial phenotype through TGF-β1effect on T cells. It seems that the TGF-β-dependent mechanisms operating in CNS maintenance under physiological conditions might become counterproductive and even destructive under chronic pathology. Accordingly, the authors show that astrocyte-specific TGF-β1 overexpression in the spinal cord of mSOD1 mice is associated with a change in the local microenvironment, including a shift toward an IFN--dominant milieu within the spinal cord, and decreased expression of a wide array of chemokines, which correlated with reduced T cell numbers, and exacerbation of disease progression.
The finding by Endo and colleagues, with respect to T cells in ALS, are consistent with previous studies, pointing to an intriguing inverse correlation between the number of CNS-infiltrating CD4+ T cells and ALS disease progression; augmented T cell recruitment to the CNS is associated with a neuroprotective effect, while T cell deficiency is associated with a worsening effect on pathology. In a study by our group, published last week (Kunis et al., 2015), we found that in the mSOD1 mouse model, recruitment of immunoregulatory cells to the spinal cord (both monocyte-derived macrophages and regulatory T cells) can shift the local milieu toward an anti-inflammatory response, associated with mitigation of pathology and increased lifespan of the mice. Interestingly, we found that the shift toward an anti-inflammatory milieu, subsequent to the recruitment of effector CD4+ T cells, was associated with an elevation in TGF-β1 in the spinal cord of the mSOD1 mice. The findings by Endo et al., together with our results, may suggest a time-dependent effect for the anti-inflammatory response within the CNS; if prematurely induced, it might block the recruitment of neuroprotective immune cells.
References:
Kunis G, Baruch K, Miller O, Schwartz M. Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS. J Neurosci. 2015 Apr 22;35(16):6381-93. PubMed.
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