Adjusting Microglia Proportions as a Basis for the Treatment of Parkinson's Disease

The balance between different types of the immune cells known as macrophages is becoming a stronger theme these days, a line of research that falls somewhere into the broad overlap between regeneration, inflammation, and aging. I've seen quite a number of interesting papers on this topic in the past year, which seems to me a leap in the level of interest shown by the research community of late. While possibly oversimplifying a more complicated reality, we can think of macrophages as having a few different types, or polarizations. The M1 polarization tends towards aggressive destruction of problem cells, the creation of inflammation, and hindrance of regeneration. The M2 polarization tends towards suppression of inflammation and other behaviors that encourage regeneration. The cancer research community would like to be able to adjust macrophage populations towards the M1 type, more willing to destroy cancerous cells, while the regenerative medicine community would like to be able to adjust macrophage populations towards the M2 type to spur enhanced regeneration and tissue maintenance.

It may be that the increased interest in macrophage polarization is a function of the emergence of tools that now allow for cost-effective attempts to shift the balance of macrophage types. The infrastructure of biotechnology is advancing rapidly, and progress spurred by falling costs is a common theme in many parts of the field. Today I'll offer up another example of macrophage polarization research, this time involving microglia, a form of macrophage resident in the central nervous system. Changes in microglia have been shown to be important in any number of age-related neurodegenerative conditions: the immune system declines with age in the brain, just as elsewhere in the body, falling into a dysfunctional and inflammatory state. This affects regeneration and tissue maintenance as is the case for macrophages beyond the brain, but microglia also have additional roles in the correct function of neurons and neural connections, an area of our biochemistry that is still comparatively poorly understood. It is possible to achieve benefits for patients by coercing more microglia into the M2, pro-regenerative polarization? In this open access paper, researchers examine the question in the context of Parkinson's disease.

Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson's Disease

A growing body of evidence suggest that neuroinflammation mediated by microglia, the resident macrophage-like immune cells in the brain, play a contributory role in Parkinson's disease (PD) pathogenesis. In the central nervous system (CNS), the innate immune response is predominantly mediated by microglia and astrocytes. Microglia play a vital role in both physiological and pathological conditions. Microglia appear to be involved in several regulatory processes in the brain that are crucial for tissue development, maintenance of the neural environment and, response to injury and promoting repair. Similar to peripheral macrophages, microglia directly respond to pathogens and maintain cellular homeostasis by purging said pathogens, as well as dead cells and pathological gene products.

Microglia participate in both physiological and pathological conditions. In the former, microglia restore the integrity of the central nervous system and, in the latter, they promote disease progression. Microglia acquire different activation states to modulate these cellular functions. When classically activated, microglia acquire the M1 phenotype, characterized by pro-inflammatory and pro-killing functions that serve as the first line of defense. The alternative M2 microglial activation state is involved in various events including immunoregulation, inflammation dampening, and repair and injury resolution.

Upon activation to the M1 phenotype, microglia elaborate pro-inflammatory cytokines and neurotoxic molecules promoting inflammation and cytotoxic responses. In contrast, when adopting the M2 phenotype microglia secrete anti-inflammatory gene products and trophic factors that promote repair, regeneration, and restore homeostasis. Relatively little is known about the different microglial activation states in PD, and the distribution of microglial M1/M2 phenotypes depends on the stage and severity of the disease. Understanding stage-specific switching of microglial phenotypes and the capacity to manipulate these transitions within appropriate time windows might be beneficial for PD therapy. The transition from the M1 pro-inflammatory state to the regulatory or anti-inflammatory M2 phenotype is thought to assist improved functional outcomes and restore homeostasis. The induction of M1 phenotype is a relatively standard response during injury. For peripheral immune cells it is thought that M1 polarization is terminal and the cells die during the inflammatory response. Although a shift from M1 to the M2 phenotype is considered rare for peripheral immune cells, microglia can shift from M1 to M2 phenotype.

To inhibit the pro-inflammatory damage through M1 activation of microglia, its downstream signaling pathways could be targeted. The M1 phenotype is induced by IFN-γ via the JAK/STAT signaling pathway and targeting this pathway may arrest M1 activation. In fact, studies show that inhibition of the JAK/STAT pathway leads to suppression of the downstream M1-associated genes in several disease models. Another approach to suppress M1 activation would be to target the pro-inflammatory cytokines such as TNF-α, IL-1β and IFN-γ, and decrease its ability to interact with its receptors on other cell types. Alternatively, molecules with the capability to activate the anti-inflammatory M2 phenotype or promote the transition of pro-inflammatory M1 phenotype to anti-inflammatory M2 could be useful in the treatment of PD. Anti-inflammatory molecules such as IL-10 and beta interferons produce neuroprotection by altering the M1 and M2 balance.

The critical role of microglia in most neurodegenerative pathologies including PD is increasingly documented through many studies. Until recently, microglial activation in pathological conditions was considered to be detrimental to neuronal survival in the substantia nigra of PD brains. Recent findings highlight the crucial physiological and neuroprotective role of microglia and other glial cells in neuropathological conditions. Studies on anti-inflammatory treatments targeting neuroinflammation in PD and other diseases by delaying or blocking microglial activation failed in many trials due to the lack of a specific treatment approach, possibly the stage of disease and an incorrect understanding of mechanisms underlying microglial activation. With the updated knowledge on different microglial activation states, drugs that can shift microglia from a pro-inflammatory M1 state to anti-inflammatory M2 state could be beneficial for PD. The M1 and M2 microglial phenotypes probably need further characterization, particularly in PD pathological conditions for better therapeutic targeting. We support targeting of microglial cells by modulating their activation states as a novel therapeutic approach for PD.


Do peripheral macrophages neatly polarize as M1/M2 aswell? The concept that microglia are simply the brain's tissue resident macrophage may be a simplification. As the authors say, microglial derive from primitive yolk sac myeloid progenitors that seed the developing brain parenchyma. However, bone marrow hematopoetic monocyte progenitors also travel to the brain, in development AND throughout all stages of life in normal and pathological circumstances, and form a somewhat heterogenous population that includes microglial cells (even fusing with local brain cells as we know from mom's with Y chromosomes of fetal origin andother studies). The question, in light of the previous discussion on allotopic expression the other day, is how do microglia wield their mitochondria in the brain to do their bidding if the usual immunogenic tool kit availible in the periphery (reactivity to mitochndrial formylatedpeptides, CpG non-methyated mtDNA fragments, cardiolipid products, etc) and the usual white blood cell suspects they attract and activate, do not so readily pass the BBB?

Posted by: john hewitt at June 28th, 2017 4:35 AM

The root issue I see as far as inflammation and radical generation by M2/M1 macrophages, whether it is in Parkinson's here, nerve regeneration as mentioned in the atherosclerosis post the other day, or salamander tail absorption / limb regrowth prior to that, is what are the mitochondria (that initiate these radicals and inflammatory sequelae) doing in each macrophage phenotype? What is their membrane potential, pH, and crucially as we now know mitos prefer to operate at 50 degrees C, what is their temperature? A primary clue I think is found in the similarities between regeneration and cancer, namely the frequent requirement for nervous innervation and likely mitochondrial transfer. Studies of regeneration have typically either focused on the requirement for macrophages as here, or critically, focused on the essential requirement for nervous re-innervation of the blastema, stump, or whatever tissue rudiment is blooming. Looking at both processes together, however, is likely critical. Yes the now emerging essential role of nervous innervation in many cancers, in particular as primary donors of transformative mitochondria is somewhat speculative and difficult to probe. (We should note that as motile blood borne elements, systemic macrophages appear largely free of nervous influence, and similarly vice-versa) But wait folks, look at this:
Optogenetic control of mitochondrial metabolism and Ca2+signaling by mitochondria-targeted opsins
When channelrhodopsins were fused at the N terminus to a tandem of four repeats of the Cox-8 mitochondria-targeting peptide these guys got them to efficiently localize to the mitochondrial inner membrane, thereby making light controllable mitochondria, ie. (Δψm)-controllable, electron transport controllable, and ATP generation controllable mitochondria. Perfect for controlling their behaviors in nerve or blood.

Posted by: john hewitt at June 28th, 2017 5:48 AM
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