key: cord-0901252-72n5rcnj
authors: He, Yonghan; Zhou, Daohong
title: Can molecular targeting the TNFα-ERK-ETS1-IL27Rα pathway keep us young and healthy by protecting HSCs from aging?
date: 2020-10-23
journal: Blood Sci
DOI: 10.1097/bs9.0000000000000060
sha: f01f4199b222e1526e4a5503ede426ba791f23b5
doc_id: 901252
cord_uid: 72n5rcnj

nan

The world's older population grows at an unprecedented rate. Today, there are about 8.5% of people worldwide (617 million) aged 65 and older today, which is projected to continue growing to nearly 17% of the world's population by 2050 (1.6 billion). World population aging has profound implications because aging represents a progressive deterioration of physiological function accompanied by an increase in vulnerability for disease and mortality. Although aging itself is not a disease, it is the greatest risk factor for most chronic human diseases, including cardiovascular and neurodegenerative disease, cancer, diabetes, and osteoarthritis; and a major contributing factor for the increased susceptibility to various infectious diseases such as COVID-19. Age-related changes in the hematopoietic and immune system likely play an important role in the pathogenesis of these diseases in part via induction of immunosenescence and inflammaging. 1 These changes have been largely attributed to hematopoietic stem cell (HSC) aging, which leads to a significant decline in HSC self-renewal and long-term hematopoietic reconstitution, a myeloid skewing (ie, increase in myeloid cell but decrease in lymphoid cell production), and clonal hematopoiesis and increased hematological malignancies. 2 Both cellintrinsic and cell-extrinsic alterations have been implicated in driving HSC aging. The cell-intrinsic mechanisms of HSC aging include increased DNA damage, 3 loss of polarity and proteostasis, 4 impaired autophagy and mitochondrial activities, 5 epigenetic reprogramming and senescence. 6, 7 The cell-extrinsic mechanisms are less studied but may include alterations in bone marrow stromal cell populations, changes in the production of hematopoietic stimulators (such as osteopontin) and inhibitors (such as CCL5) by the stromal cells, and increased production of inflammatory cytokines. 8 However, how these cell-extrinsic factors communicate with HSCs to promote HSC aging has not been well established.

In a recent Blood publication, 9 Dr. Jianwei Wang's group investigated the mechanistic link between age-related inflammation and HSC aging. They found that aging is associated with an upregulation of interleukin 27 receptor a (IL27Ra) expression in HSCs from mouse bone marrow, resulting in a significant expansion of IL27Ra + HSCs. IL27Ra + HSCs from both young and old mice exhibited all the phenotypes of aged or senescent HSCs, including inability to self-renew, produce long-term hematopoietic reconstitution, and differentiate into both myeloid and lymphoid cells in a balanced manner after transplantation. In contrast, IL27Ra -HSCs from both old mice and HSCs from old IL27Ra knockout (IL27Ra À/À ) mice exhibited significant improvement in HSC functions compared to IL27Ra + HSCs from the same aged mice. These findings indicate that IL27Ra can be used as a biomarker for aged and senescent HSCs. Next, they investigated the underlying mechanisms contributing to the agerelated upregulation of IL27Ra in HSCs. They found that NF-kB and EST1 are important transcription factors that regulate the expression of IL27Ra. However, aging is associated with an increased expression of phosphorylated ERK and ETS1 in HSCs, but with no changes in the NF-kB activation. The activation of the ERK-ETS1 pathway and increased expression of IL27Ra in old HSCs may be attributable to the stimulation by the HSC-extrinsic proinflammatory cytokine TNFa. This is because mouse bone marrow plasma from old mice contained a significantly higher level of TNFa than that from young mice. TNFa stimulated the expression of IL27Ra in c-Kit + Sca1 + Lineage -(KLS) cells and HSCs in vitro and in vivo, respectively, in an ETS1-dependent manner. The upregulation of IL27Ra in HSCs is likely responsible for mediating TNFa-induced HSC dysfunction because knockout IL27Ra could prevent TNFa-induced HSC dysfunction. Therefore, these findings are highly significant by providing the first link between cell-extrinsic and cell-intrinsic communications that lead to HSC aging via the activation of the TNFa-ERK-ETS1-IL27Ra pathway. It will be of great interest to determine whether molecular targeting this pathway with a small molecule inhibitor or an antibody has the potential to be developed as a novel therapeutic strategy to slowdown HSC aging, which may lead to reduced inflammaging and improvement of hematopoietic and immune functions, particularly under various age-related pathological conditions in which TNFa production is upregulated systemically or locally in the bone marrow microenvironment. However, cautions have to be take into consideration before translating this approach into the clinic because IL27Ra + HSCs may be primarily responsible for emergency hematopoiesis in the fight against bacterial infection as shown by the authors in this publication.

HSC Aging and Senescent Immune Remodeling

Aging of hematopoietic stem cells

Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age

Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation

Autophagy maintains the metabolism and function of young and old stem cells

Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice

Haematopoietic stem cell activity and interactions with the niche

Aging-induced IL27Ra signaling impairs hematopoietic stem cells