Understanding Microglia Cells Functions

During embryonic development, primitive yolk sac myeloid progenitors enter the brain and differentiate into microglial cells. It is usually estimated that around 10% of the adult brain cells are microglia cells. Microglia can develop into proinflammatory/classically activated M1 or anti-inflammatory activated M2 phenotypes depending on the signals present at different stages after brain lesions. M1/proinflammatory microglia produces proinflammatory mediators and ROS that exacerbate neuronal death. Alternatively, M2/immunoregulatory microglia induce brain repair and regeneration, produce growth factors and anti-inflammatory cytokines to protect neurons and resolve inflammation. Several subclasses of M2/immunoregulatory activation have been identified. The M2a activation state has a main function of suppression inflammation. A second state of alternative activation is classified as M2c, which has been suggested to restore the tissue after the inflammatory process has been attenuated. M2b has been involved in both pro- or anti-inflammatory responses and related to memory immune responses. Collectively, M2 phenotype cells are involved in anti-inflammatory, debris clearance, extracellular matrix deposition and angiogenesis functions in the brain. Progression from the proinflammatory /M1 to immunoregulatory/M2 phenotype is necessary to efficiently counteract brain lesions. However, when this process is dysregulated, the persistent release of inflammatory cytokines and ROS induces neuron death and enhances brain damage. Persistently proinflammatory M1 microglia in the brain is the key factor for the development of neurodegerative disorders like multiple sclerosis, Alzheimer’s disease and Parkinsonian disease. Of note, the FDA -approved drug glatiramer acetate (GA) for multiple sclerosis treatment, works by inducing Th1 to Th2 shift, resulting in the production of anti-inflammatory cytokines like IL-4 that polarize the microglia into M2 anti-inflammatory phenotype.

Cytokines like TNF-α, IL-6, IL-1β and interferon -γ (INF-γ) and several chemokines, in addition to the level of microglia NADPH-oxidase activation are essential to shift the microglia to pro-inflammatory type M1. Ang-II via its AT₁ receptor, is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects resulting in the shift to M1 type. However, the anti-inflammatory cytokines like IL-4, IL-10 and peroxisome proliferator activated gamma receptor (PPAR γ) agonists are polarizing the microglia towards the anti-inflammatory M2.

The angiotensin receptor blocker (ARB) group is heterogenous, with some members notably Telmisartan and to lesser extent Candesartan, exhibiting a pleiotropic profile, not only blocking AT₁ receptor but also activating PPARγ an anti-inflammatory, and pro-metabolic nuclear receptor thereby helps in shifting the microglia cells towards the anti-inflammatory M2 type.

Alzheimer’s disease is the most common form of dementia and is characterized by the presence of neurofibrillary tangles of hyperphosphorylated Tau and extracellular deposits of the peptide amyloid β (Aβ), forming neuritic plaques. Another key feature of Alzheimer’s disease is the presence of prominent neuroinflammation. There are several ways for Aβ clearance from the brain. Amyloid β can be directly shuttled out of the brain via protein complexes such as LRP1 and apolipoprotein E, which can bind extracellular Aβ and transport them to the blood brain barrier, where they are then shuttled to the other side. Extracellular Aβ in CNS interstitial fluid is moved into the CSF via the newly discovered glymphatic pathway. Finally, Aβ can be cleared via phagocytosis and degradation by resident CNS immune cells, such as microglia, astrocytes and possibly neurons. M2 type is the key player in the process of phagocytosis and clearance of Aβ from the brain.^1,2,3,4

The treatment of ARB with their ability to shift the microglia towards M2 type has improved the cognition in many rodent models of Alzheimer’s disease in doses that did not significantly lower blood pressure. Therefore, administration of ARBs to hypertensive patients, reduced the risk not only of Alzheimer’s disease but also for vascular dementia.⁵ In controlled clinical trials, several ARBs not only limit stroke-induced damage, protecting executive function and cognition, but also reduce hypertension and diabetes, major risk factors for stroke.^6,7,8,9,10

Parkinson’s disease is characterized by enhanced NADPH-oxidase activity, enhanced uncontrolled inflammatory processes, increased TNF-α production, regulation of α-synuclein, reduction of brain neurotrophic factors and decreased activation of PPARγ. The use of most potent ARBs Candesartan and Telmisartan is considered among the new treatments for Parkinson’s disease.^3,7

In vivo and vitro studies revealed that the ARB Olmesartan increased neurite outgrowth and acetyltransferase activity in primary cultures of ventral spinal cord and enhanced survival of motor neurons after unilateral section of the sciatic nerve. Therefore, Olmesartan is considered as a possible therapeutic agent in disorders leading to degeneration of motor neurons, such as amyotrophic lateral sclerosis.¹¹

References

1. Cherry, J.; Olschowka, J.; O’Banion, M. Neuroinflammation And M2 Microglia: The Good, The Bad, And The Inflamed. Journal of Neuroinflammation 2014, 11, 98.
2. Labandeira-Garcia, J.; Costa-Besada, M.; Labandeira, C.; Villar-Cheda, B.; Rodríguez-Perez, A. Insulin-Like Growth Factor-1 And Neuroinflammation. Frontiers in Aging Neuroscience 2017, 9.
3. Villapol, S.; Saavedra, J. Neuroprotective Effects Of Angiotensin Receptor Blockers. American Journal of Hypertension 2014, 28, 289-299.
4. Saavedra, J. Evidence To Consider Angiotensin II Receptor Blockers For The Treatment Of Early Alzheimer’S Disease. Cellular and Molecular Neurobiology 2016, 36, 259-279.
5. Saavedra, J. Beneficial Effects Of Angiotensin II Receptor Blockers In Brain Disorders. Pharmacological Research 2017, 125, 91-103.
6. Davies, N.; Kehoe, P.; Ben-Shlomo, Y.; Martin, R. Associations Of Anti-Hypertensive Treatments With Alzheimer's Disease, Vascular Dementia, And Other Dementias. Journal of Alzheimer's Disease 2011, 26, 699-708.
7. Horiuchi, M.; Mogi, M. Role Of Angiotensin II Receptor Subtype Activation In Cognitive Function And Ischaemic Brain Damage. British Journal of Pharmacology 2011, 163, 1122-1130.
8. Li, N.; Lee, A.; Whitmer, R.; Kivipelto, M.; Lawler, E.; Kazis, L.; Wolozin, B. Use Of Angiotensin Receptor Blockers And Risk Of Dementia In A Predominantly Male Population: Prospective Cohort Analysis. BMJ 2010, 340, b5465-b5465.
9. Mogi, M.; Iwanami, J.; Horiuchi, M. Roles Of Brain Angiotensin II In Cognitive Function And Dementia. International Journal of Hypertension 2012, 2012, 1-7.
10. Hajjar, I.; Hart, M.; Chen, Y.; Mack, W.; Novak, V.; C. Chui, H.; Lipsitz, L. Antihypertensive Therapy And Cerebral Hemodynamics In Executive Mild Cognitive Impairment: Results Of A Pilot Randomized Clinical Trial. Journal of the American Geriatrics Society 2013, 61, 194-201.
11. Iwasaki, Y.; Ichikawa, Y.; Igarashi, O.; Kinoshita, M.; Ikeda, K. Trophic Effect Of Olmesartan, A Novel AT1R Antagonist, On Spinal Motor Neuronsin Vitroandin Vivo. Neurological Research 2002, 24, 468-472.

Author

Ehab Farag, MD

The Cleveland Clinic

Cleveland, Ohio