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Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, Joseph B. Caspase signalling controls microglia activation and neurotoxicity. Nature. 2011 Apr 21;472(7343):319-24. PubMed.
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University of Southern California
On the basic biology front, Burguillos et al. present a thought-provoking idea that the caspase-3/7/8 pathway regulates innate immune activation in microglia. Until now, the dogma has been that caspases are critical cogs in the apoptosis wheel, where they have been thought to function almost exclusively. In the immunology world, our thinking began to shift with the discovery of the inflammasome, an intracellular pathogen recognition system that requires caspase-1 activation to cleave pro-interleukin 1β to the active cytokine. This paper shows that caspases 3, 7, and 8 are enablers of Toll-like receptor activation in microglia (and likely other innate immune cells, e.g., macrophages and dendritic cells). This is certainly interesting and will no doubt lead to a flurry of activity in search of the molecular mechanism for these findings.
The authors speculate that the caspase-3/7/8 pathway may represent an attractive candidate for therapeutic intervention in Alzheimer’s and Parkinson’s diseases, given that this pathway is upregulated in patients’ brains. Their idea is to block this cascade and thereby shut down neuroinflammation as a treatment for these diseases. In the context of AD, though, it deserves mentioning that generally inhibiting inflammation via NSAIDs did not produce a positive signal for primary prevention in a randomized controlled trial (ADAPT). In fact, recent evidence from Tom Montine and John Breitner actually showed greater neuritic plaque load in brains of NSAID users that converted to AD (Sonnen et al., 2010). It is therefore unclear that the principle of inhibiting inflammation to provide AD prophylaxis is a valid one. We, and others, have revised our thinking to a more contemporary view: There are multiple forms of microglial “activation,” some of which are deleterious, and others, beneficial. So the question becomes, Which form does caspase-3/7/8 endorse?
References:
Sonnen JA, Larson EB, Walker RL, Haneuse S, Crane PK, Gray SL, Breitner JC, Montine TJ. Nonsteroidal anti-inflammatory drugs are associated with increased neuritic plaques. Neurology. 2010 Sep 28;75(13):1203-10. PubMed.
Third Rock Ventures
The experiments in the paper by Burguillos et al. focus mainly on in vitro work with BV-2 cells, myc-raf immortalized mouse microglia. Stimulating these cells with LPS, the authors showed that caspases, enzymes involved in apoptosis and inflammation, signal via PKC-Δ to mediate standard inflammatory endpoints such as NFκB activation. This finding is novel. PD or AD relevance would need to come from clinical trials targeting one of these enzymes. The blocking of apoptosis-mediating enzymes, however, would be fraught with concerns about induction of tumors or autoimmunity. The in vivo studies here involved intrastriatal injection of LPS to confirm that in vitro biochemistry could be recapitulated in vivo.
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