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Review
. 2020 May;98(5):633-650.
doi: 10.1007/s00109-020-01904-z. Epub 2020 Apr 11.

ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease

Antero Salminen  1 , Kai Kaarniranta  2   3 , Anu Kauppinen  4
Affiliations
Review

ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease

Antero Salminen et al. J Mol Med (Berl). 2020 May.

Abstract

The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.

Keywords: Ageing; Immunometabolism; Immunosenescence; Immunosuppression; Inflammaging; Neurodegeneration.

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Conflict of interest statement

The authors state that there are no personal or institutional conflicts of interest.

Figures

Fig. 1
Fig. 1
ER stress evokes inflammatory responses via the activation of three branches of ER stress sensors. PERK, IRE1, and ATF6 signaling pathways induce the expression of inflammatory mediators by activating AP-1, CHOP, and NF-κB transcription factors. IRE1 and PERK signaling can also trigger TXNIP signaling which activates inflammasomes. There are several review articles depicting the UPR pathways more thoroughly, both the basic pathways [1, 17, 26, 27, 31] and those related to inflammation and immunity [16, 81, 82]. Abbreviations: AKT, protein kinase B; AP-1, activator protein 1; ASK1, apoptosis signal-regulating kinase 1; ATF, activating transcription factor; CHOP, CCAAT-enhancer-binding protein homologous protein; eIF2α, eukaryotic initiation factor 2α; ER, endoplasmic reticulum; IκB, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor; IKK, IκB kinase; IRE1, inositol-requiring protein 1; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; NOD, nucleotide-binding oligomerization domain-containing protein; PERK, protein kinase RNA-like ER kinase; TRAF2, TNF receptor-associated factor 2; TXNIP, thioredoxin-interacting protein; XBP1, X-box binding protein 1
Fig. 2
Fig. 2
A schematic presentation on the induction of immunosuppression by ER stress. The ER stress of host tissues, containing, e.g., senescent cells, stimulates the secretion of inflammatory mediators which consequently provoke myelopoiesis in the bone marrow. Increased numbers of myeloid cells will be recruited into lymphoid and peripheral tissues. Inflammatory mediators secreted by host tissues trigger ER stress in infiltrated immune cells and concurrently enhance their immunosuppressive properties. A continual immunosuppression in inflamed tissues further impairs the homeostasis of tissues, e.g., by impairing proteostasis and enhancing cellular senescence. This ER stress-provoked vicious cycle degenerates tissues with aging and brains in Alzheimer’s disease. Abbreviations: MDSC, myeloid-derived suppressor cell; Mreg, regulatory macrophage; Treg, regulatory T cell.
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