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The potential importance of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of Alzheimer’s disease

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Abstract

The exact cause of Alzheimer’s disease (AD) is still unknown, but the deposition of amyloid-β (Aβ) plaques and chronic inflammation indicates that immune disturbances are involved in AD pathogenesis. Recent genetic studies have revealed that many candidate genes are expressed in both microglia and myeloid cells which infiltrate into the AD brains. Invading myeloid cells controls the functions of resident microglia in pathological conditions, such as AD pathology. AD is a neurologic disease with inflammatory component where the immune system is not able to eliminate the perpetrator, while, concurrently, it should prevent neuronal injuries induced by inflammation. Recent studies have indicated that AD brains are an immunosuppressive microenvironment, e.g., microglial cells are hyporesponsive to Aβ deposits and anti-inflammatory cytokines enhance Aβ deposition. Immunosuppression is a common element in pathological disorders involving chronic inflammation. Studies on cancer-associated inflammation have demonstrated that myeloid-derived suppressor cells (MDSCs) have a crucial role in the immune escape of tumor cells. Immunosuppression is not limited to tumors, since MDSCs can be recruited into chronically inflamed tissues where inflammatory mediators enhance the proliferation and activation of MDSCs. AD brains express a range of chemokines and cytokines which could recruit and expand MDSCs in inflamed AD brains and thus generate an immunosuppressive microenvironment. Several neuroinflammatory disorders, e.g., the early phase of AD pathology, have been associated with an increase in the level of circulating MDSCs. We will elucidate the immunosuppressive armament of MDSCs and present evidences in support of the crucial role of MDSCs in the pathogenesis of AD.

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Abbreviations

Aβ:

Amyloid-β

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

ARG1:

Arginase 1

Breg:

Regulatory B cell

CAA:

Cerebral amyloid angiopathy

C/EBPβ:

CCAAT/enhancer-binding protein β

CHOP:

C/EBP-homologous protein

FOXP3:

Forkhead box P3

GCN2:

General control nonderepressible 2 kinase

HIF-1α:

Hypoxia-inducible factor-1α

HMGB1:

High mobility group box 1

HSV1:

Herpes simplex virus type 1

IDO:

Indoleamine-pyrrole 2,3-dioxygenase

MCI:

Mild cognitive impairment

MDSC:

Myeloid-derived suppressor cell

MIF:

Macrophage migration inhibitory factor

NF-κB:

Nuclear factor-κB

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOX2:

NADPH2 oxidase 2

NRF2:

Nuclear factor-erythroid 2-related factor 2

NSAID:

Non-steroidal anti-inflammatory drug

PD-L1:

Programmed death-ligand 1

PGE2:

Prostaglandin E2

STAT:

Signal transducer and activator of transcription

TGF-β:

Transforming growth factor-β

TNF-α:

Tumor necrosis factor-α

Treg:

Regulatory T cell

TREM2:

Triggering receptor expressed on myeloid cells 2

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Acknowledgements

This study was financially supported by the Grants from the Terveyden Tutkimuksen Toimikunta of Academy of Finland (AK297267, AK307341, and KK296840), the Kuopio University Hospital VTR Grant (KK5503743), the Emil Aaltonen Foundation, the Finnish Cultural Foundation, and the Finnish Eye Foundation. The authors thank Dr. Ewen MacDonald for checking the language of the manuscript.

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Authors and Affiliations

  1. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Antero Salminen

  2. Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Kai Kaarniranta

  3. Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, 70029 KYS, Kuopio, Finland

    Kai Kaarniranta

  4. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Anu Kauppinen

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  1. Antero Salminen
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  2. Kai Kaarniranta
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  3. Anu Kauppinen
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Correspondence to Antero Salminen.

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Salminen, A., Kaarniranta, K. & Kauppinen, A. The potential importance of myeloid-derived suppressor cells (MDSCs) in the pathogenesis of Alzheimer’s disease. Cell. Mol. Life Sci. 75, 3099–3120 (2018). https://doi.org/10.1007/s00018-018-2844-6

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  • DOI: https://doi.org/10.1007/s00018-018-2844-6

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