Cycle 1 project 6

Natural control of inflammation in preactive Multiple Sclerosis lesions

PhD student: Shailender Singh, India
Home Institute: Amsterdam Neuroscience; Principle Investigator: Sandra Amor
Host Institute: European Neuroscience Institute Göttingen; Principle Investigator: Wolfgang Brück

Executive Summary
The earliest pathological sign of damage in the CNS in multiple sclerosis (MS) are clusters of activated microglia in otherwise normal-appearing white matter. The frequency at which preactive lesions are found in MS suggest that most spontaneously resolve, without progressing to an active demyelinating stage. Microglia activation at this stage may therefore reflect immune-regulatory or immune-suppressive rather than pro-inflammatory activity.

Small heat shock proteins (sHSPs) may play an important role in preactive lesions since we have shown that sHSPs accumulate in oligodendrocytes in preactive lesions, directly contact the microglial surface. Moreover in vitro sHSPs activate microglia. Initial data shows that such activation induces an immune-regulatory phenotype typified by production of IL-10, TGF-b and TNF-a, and suppression of IL-12, consistent with the previously demonstrated anti-inflammatory effects of soluble sHSPs in animal models.

We therefore hypothesize that pre-active lesions reflect a mild form of reversible neuroinflammation, governed by predominantly immune-regulatory and neuroprotective processes. We believe pre-active lesions thus hold the key to understanding natural mechanisms of immune regulation and repair in the human CNS.

The project will examine the idea that activated microglia in pre-active MS lesions represent immune-regulatory and/or wound-healing microglia, engaged in the resolution of local insults. On the evidence from previous studies and our preliminary studies it is further hypothesized that nearby stressed oligodendrocytes provide the direct local trigger for such activation and clustering of microglia, likely involving signalling by small HSPs.

The project will address the following questions:

1. Which molecular markers typify immune-regulatory human microglia?
This will allow the characterization of microglia phenotypes in preactive lesions. The molecular profile of distinct phenotypic states of microglia has obvious relevance also for other CNS disorders.

2. Does the immune-regulatory state of microglia lead to both anti-inflammatory and neuroprotective factors?
By examining the in vitro effect of factors produced by human microglia with an immune-regulatory phenotype on the activity of T cells, or survival of neurons, functional validation can be obtained of this state.

3. Which endogenous signals from stressed oligodendrocytes induce the immune-regulatory phenotype in microglia?
Examination of microglia-activating signals from oligodendrocytes should clarify whether the previously observed sHSP-induced response is unique in this context, or part of a signaling system between oligodendrocytes and microglia. This should provide the read-out marker(s) for question 4 and provide new leads for substances that can be used to manipulate the activation phenotype in microglia.

4. Which factors in the CNS drive the apparent stress in oligodendrocytes in pre-active MS lesions, and the accumulation of microglia-activating signals such as small HSPs?
By examining the factor(s) that drive the stress response of oligodendrocytes, inducing accumulation of the microglia-activating factors we will have a better understanding of which induces pre-active MS lesions.