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

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.

Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases

“…The situation is reminiscent of the compensatory immunosuppression encountered in inflammatory diseases (see above). It is also known that different cellular stresses, e.g., oxidative stress and ER stress, are potent inducers of inflammation which enhances the differentiation and expansion of immunosuppressive MDSCs [ 60 – 62 ]. Ruhland et al [ 20 ] demonstrated that the upregulation of senescent stromal cells in mouse skin provoked inflammation which promoted the appearance of an immunosuppressive microenvironment, i.e., senescent cells augmented the levels of MDSCs and Tregs in mouse skin.…”

Immunosenescence is both functional/adaptive and dysfunctional/maladaptive

“…Furthermore, it was shown that the MDSCs induce the increase of Tregs [170,183]. In this way, there is an immunosuppressive network which is created as individuals are aging as coined by Salminen et al [184]. It seems that TGF-β, IL-10, and NO, secreted by MDSCs, are the major soluble mediators maintaining the functions of this age-related immunosuppressive network [185].…”

“…Together, the immunosuppressive network increase with aging may have several pathological consequences [184,185], but however, in the spirit of immunobiography, this can also be considered an adaptation to decrease the lifelong activation process of the innate immune system (innate immune memory) but unfortunately in the meantime downregulate adaptive immune activation.…”

Tumor Microenvironment Uses a Reversible Reprogramming of Mesenchymal Stromal Cells to Mediate Pro-tumorigenic Effects

“…Like aging processes, cancers environment is characterized by a chronic inflammation (“inflammaging”) and cellular senescence (“immunosenescence”). The role of stromal cells’ immunomodulation in shaping a senescent microenvironment in broad spectrum of human malignancies, especially tumorigenesis, has been documented extensively [for review see Salminen et al (2020) , Thomas et al (2020) ]. For instance, BM stromal cells from patients with myelodysplastic syndrome display a senescence phenotype induced by S100A9-induced Toll-like receptor 4 (TLR4), NLRP3 inflammasome activation and IL-1β secretion ( Shi et al, 2019 ).…”