Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Salminen, Antero; Kaarniranta, Kai; Kauppinen, Anu

doi:10.1007/s00018-019-03048-x

Cited by 105 publications

(113 citation statements)

References 236 publications

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“…Such enhanced myelopoiesis propagates inflammation from the bone marrow to the adipose tissue and the vasculature and contributes to the increased production of TNF-α, IL-6, IL-1, and C-reactive protein, leading to insulin resistance ( 130 , 131 ). Further, low-grade inflammation, persistent myelopoiesis, and MDSC expansion have been proposed as potent inducers of immunosenescence in age-related immune deficiency ( 132 ). Therefore, PD-1 blockade in patients with metabolic comorbidities, and in the elderly, might exacerbate persistent myelopoiesis and systemic inflammation.…”

Section: Signaling and Function Of The Pd-1 Pathway In Innate Immune mentioning

confidence: 99%

Revisiting the PD-1 pathway

et al. 2020

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Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

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Section: Signaling and Function Of The Pd-1 Pathway In Innate Immune mentioning

confidence: 99%

Revisiting the PD-1 pathway

et al. 2020

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“…The numerical reduction in naïve T cells and TCR-reduced repertoire result in T cells dysfucntion 25 . Similarly, there is a decline in B cells and a reduction in antibody production 26 . B cells follow a well-defined developmental process, starting from naïve cells that do not produce specific antibodies isotype, to the establishment of peripheral B cell pools that maintains maturity through self-renewal 27 .…”

Section: Inflammagingmentioning

confidence: 99%

Age-related cerebral small vessel disease and inflammaging

Huang

Cai

et al. 2020

Cell Death Dis

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The continued increase in global life expectancy predicts a rising prevalence of age-related cerebral small vessel diseases (CSVD), which requires a better understanding of the underlying molecular mechanisms. In recent years, the concept of “inflammaging” has attracted increasing attention. It refers to the chronic sterile low-grade inflammation in elderly organisms and is involved in the development of a variety of age-related chronic diseases. Inflammaging is a long-term result of chronic physiological stimulation of the immune system, and various cellular and molecular mechanisms (e.g., cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metaflammation, gut microbiota dysbiosis) are involved. With the deepening understanding of the etiological basis of age-related CSVD, inflammaging is considered to play an important role in its occurrence and development. One of the most critical pathophysiological mechanisms of CSVD is endothelium dysfunction and subsequent blood-brain barrier (BBB) leakage, which gives a clue in the identification of the disease by detecting circulating biological markers of BBB disruption. The regional analysis showed blood markers of vascular inflammation are often associated with deep perforating arteriopathy (DPA), while blood markers of systemic inflammation appear to be associated with cerebral amyloid angiopathy (CAA). Here, we discuss recent findings in the pathophysiology of inflammaging and their effects on the development of age-related CSVD. Furthermore, we speculate the inflammaging as a potential target for future therapeutic interventions to delay or prevent the progression of the age-related CSVD.

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“…tumors, obesity, chronic infections, and neurodegenerative diseases, the impaired capacity of effector immune cells exerts detrimental effects on the maintenance of tissue homeostasis. The age-related immunosenescence evokes very similar changes in the phenotypes of immune cells as can be induced by the MDSC-driven immunosuppression [187]. Currently, it needs to be clarified whether the immunosenescent phenotype of immune cells is generated by the activation of the immunosuppressive network.…”

Section: Chronic Immunosuppression Disturbs the Homeostasis Of Tissuesmentioning

confidence: 99%

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

2020

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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.

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Immunosenescence: the potential role of myeloid-derived suppressor cells (MDSC) in age-related immune deficiency

Cited by 105 publications

References 236 publications

Revisiting the PD-1 pathway

Revisiting the PD-1 pathway

Age-related cerebral small vessel disease and inflammaging

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

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