Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging.
With age, a chronic, systemic and low grade inflammatory process is referred to as inflammaging, which is associated with immunosenescence and age-related diseases [1][2]. There is evidence indicating that inflammaging occurs in hematopoiesis under chronic inflammatory stress. Interestingly, inflammation-associated stress hematopoiesis is very similar as age-associated hematopoiesis, discussed above. For example, chronic inflammatory signals cause the expansion of HSC and GMP and a reduction of CLP and RBC [3][4]. Similar phenotypes emerge during experimental spondyloarthritis in which mice developed non-resolving inflammation [5]. In addition, consecutive injections of LPS dramatically suppressed erythropoiesis [6]. Most importantly, increasing evidence demonstrates that multiple pro-inflammatory cytokines, including IL-1β [7][8], TNF-α [9], IL-6 [8] and TGFβ1 [10], are present at increased levels in aged BM (Table 12). The inhibition of both IL-1β and TNF-α in aged mice attenuated myelopoiesis [11]. This indicates that aged HSCs are exposed to a niche containing more pro-inflammatory cytokines, which likely contributes to the age-associated HSC dysfunctions. This also suggests that the inhibition of inflammatory responses may rejuvenate aged HSC.
Table 1. The role of pro-inflammatory cytokines in hematopoiesis and their altered expression during aging.
Stimuli |
---|
Stimuli |
Source |
---|
Source |
Effects on HSC |
---|
Effects on HSC |
Change with Age |
---|
Change with Age |
Reference |
---|
Reference |
Up | [3,4,36,42,82] |
||||
TNF-α |
Macrophages, T cells, NK cells |
Myeloid differentiation |
Up |
[37,42] |
|
IL-6 |
MSCs, macrophages |
Myeloid differentiation |
Up |
[4,83] |
|
GM-CSF |
MSCs, ECs, macrophages, T cells |
Myeloid differentiation |
|
[75] |
[ |
26 |
] |
[ |
27 |
] |
| |||||
IFN-α |
Plasmacytoid dendritic cells, macrophages |
Transient proliferation Impaired repopulation potential Exhaustion |
|
[77–79] |
|
IFN-γ |
T cells, Th1 cells, macrophages |
Proliferation Impaired repopulation potential Exhaustion |
|
[80,81] |
|
IL1-β |
Monocytes, macrophages, ECs, |
Myeloid differentiation Impaired repopulation potential | |||
G-CSF |
MSCs, ECs |
Myeloid differentiation |
|
[84,85] |
|
TGFβ1 |
MSCs, Mks |
Quiescence Expansion of myeloid-biased HSC |
Up |
[2,69] |
|
LPS |
Gram-negative bacterial infections |
Proliferation Impaired repopulation potential |
|
[48,86] |
IFN-α | Plasmacytoid dendritic cells, macrophages | Transient proliferationImpaired repopulation potentialExhaustion | [12][13][14] | |
IFN-γ | T cells, Th1 cells, macrophages | ProliferationImpaired repopulation potentialExhaustion | [15][16] | |
IL1-β | Monocytes, macrophages, ECs, | Myeloid differentiationImpaired repopulation potential | Up | [3][4][17][18][19] |
TNF-α | Macrophages, T cells, NK cells | Myeloid differentiation | Up | [20][18] |
IL-6 | MSCs, macrophages | Myeloid differentiation | Up | [4][21] |
GM-CSF | MSCs, ECs, macrophages, T cells | Myeloid differentiation | [22] | |
G-CSF | MSCs, ECs | Myeloid differentiation | [23][24] | |
TGFβ1 | MSCs, Mks | QuiescenceExpansion of myeloid-biased HSC | Up | [2][25] |
LPS | Gram-negative bacterial infections | ProliferationImpaired repopulation potential |
ECs: endothelial cells, MSCs: mesenchymal stromal cells, Mks: megakaryocytes.
Inflammatory signals activate HSC and promote myelopoiesis [3317][5][4327][4428][4529][4630]. This response is beneficial in combatting infection, but chronic exposure to inflammatory insults impairs HSC self-renewal and causes stem cell loss. Most inflammatory stimuli have been reported to affect HSC multi-lineage differentiation and long-term repopulation potential (Table 2). HSCs grown in liquid culture with IL-1β produced more mature myeloid cells [3]. Furthermore, mice that were chronically exposed to IL-1β displayed increased myeloid cells at the expense of lymphoid cells. HSCs isolated from these mice displayed myeloid-biased differentiation potential and significant reduced self-renewal [3]. Of note, the impairment of HSC recovered after treatment, which is probably due to the reestablished quiescence. TNF-α also promotes myeloid regeneration in vitro [3317][4731]. Although no major changes in lineage distributions were observed from TNF-α-treated HSCs, these HSCs had severely compromised reconstitution abilities, which, similar to effects of IL-1β, recovered upon extra resting periods [3][3317]. This demonstrates a transient impairment of the engraftment potential of IL-1β and TNF-a-treated HSCs [3][3317]. Consistently, acute lipopolysaccharide (LPS) also induced transient changes in hematopoiesis, affecting epigenetic modifications and HSC gene expression [4832]. Mice transplanted with LPS pre-stimulated HSCs displayed high survival against secondary bacterial infection [4832]. However, chronic LPS treatment attenuated HSCs’ self-renewal and competitive repopulation activity [3519]. Thus, HSCs respond differently to acute and chronic inflammation, and only chronic and continuous inflammation mimics the aging-associated functional declines.
To date, we have limited knowledge of the mechanisms by which inflammatory signals regulate HSC function. Under chronic LPS exposure, the functions of HSCs were impaired in a TLR4-TRIF-ROS-p38-pathway dependent manner [3519]. C/EBPβ is required for LPS-induced memory, which improves myeloid differentiation and the resistance to secondary infection [4832]. The loss of C/EBPβ attenuates an IL-1β-driven myeloid gene program and expands hematopoietic stem and progenitor cells (HSPCs) [4630]. It also has been shown that the induction of myeloid differentiation by IL-1β and TNF-α is likely due to the activation of PU.1 [3][4024][4731] and mice lacking the PU.1 upstream regulatory severely attenuated myeloid differentiation. The overexpression of PU.1 has been shown to accelerate the myeloid output of HSCs in vitro [3]. In addition, the TNF-α-dependent activation of PU.1 is directly regulated via NF-κB-dependent signaling [3317][4731]. Actually, the transient impairment of HSCs induced by TNF-α correlates with both cell cycle activation and the status of the NF-κB pathway [3317], suggesting that this pathway is of vital importance for inflammatory hematopoiesis. Interestingly, NF-κB was shown to become activated in aged HSCs, documented by elevated phosphorylation and translocation in the nucleus [4933][9][5034]. This suggests that an active inflammatory response exists in aged HSCs at steady state and raises the possibility that NF-κB signaling pathway is a potential target to achieve rejuvenation of aged HSC.