Inflammation, often defined as a protective immune response to infection and tissue damage, is mediated by pro-inflammatory cytokines and chemokines (produced by stressed or damaged cells) and sensed by effector cells that coordinate the system and/or local responses.
It is now recognized that hematopoietic stem cells (HSCs) play a key role in the systemic inflammatory response, enabling the integration of external inflammatory cues into the cellular response and establishing a demand-adaptation axis between peripheral stress and hematopoietic response in the bone marrow. In recent years, a large number of new studies have taken a deeper look at how the function of hematopoietic stem cells is affected by inflammation and how these responses contribute to the aging and tumorigenesis of hematopoietic stem cells. Effect of inflammation-inducing factors on hematopoietic stem cell biology
J. Exp. Med. 2021 Vol. 218 No. 7 and 20201541
1. Infectious DiseasesKing and Goodell (2011) defined four different mechanisms by which infectious diseases affect hematopoietic stem cell biology. The first two mechanisms work through direct action on hematopoietic stem cells: (1) direct infection and (2) direct recognition of pathogens by PRR. The other two mechanisms are indirect: (3) through pro-inflammatory cytokines released by other cells and (4) through alterations in the bone marrow microenvironment
Nat. Rev. Immunol. 2011 Although there are significant differences between different models of infection, there are some conserved features: (a) infection-derived inflammation often leads to decreased hematopoietic stem cell function, including increased proliferation associated with myeloid bias; (b) decreased hematopoietic stem cell function is most commonly associated with chronic infection, suggesting that long-term inflammation may have a cumulative effect on hematopoietic stem cell function; (c) inflammatory cytokines can act directly on hematopoietic stem cells or indirectly cause bone marrow niche cells (eg, mesenchymal cells, endothelial cells and hematopoietic cells, etc.) produce secondary inflammatory signals. 2. The gut bacterial microbiota is emerging as a key regulator of hematopoietic function. Regarding the effect of microbiota on HSPCs pool size, Balmer et al. (2014) showed that germ-free (GF) mice (mice lacking microbiota) or antibiotic-treated specific pathogen–free (SPF) mice (carrying >100 bacterial populations, but no known mouse pathogen) had lower steady-state HSPC numbers compared to untreated SPF mice. For further evidence, antibiotic-treated mice showed a reduction in microbiota and a pool of hematopoietic stem cells that was also reduced to a similar level as that of STAT1 knockout mice. These data suggest that the cytokine-dependent STAT1 signaling pathway, stimulated by the microbiota, maintains a normal number of bone marrow hematopoietic stem cells. Microbiome molecules (including bacterial DNA, etc.), which reach the bone marrow, are sensed by TLRs of CX3CR1+ monocytes, produce inflammatory cytokines (TNF-α, IL-1, IL-6, etc.), regulate HSPC pool size and its differentiation potential. 3. Carcinogens Carcinogens include any substance, radionuclide or radiation that promotes the formation of cancer. Long-term bone marrow damage mediated by carcinogens such as ionizing radiation (IR) and chemotherapy (CT) has been attributed to direct effects on hematopoietic stem cells and the bone marrow environment. These effects include induction of apoptosis, differentiation, senescence, and/or damage to the BM hematopoietic stem cell niche.
Transl. Cancer Res. 2013 chemoradiotherapy induces rapid and dynamic secretion of inflammatory cytokines and chemokines, including IL-1α/β, IL-6, IL-8, IFN-α/βTNF-αCXCL9, CCL2, CCL3, GM-CSF, etc. 4. Inflammatory DiseasesInflammatory diseases are a series of diseases caused by dysregulated immune responses, resulting in chronic inflammation and/or periodic inflammatory "flare-ups" that may affect hematopoietic stem cell function. But broadly speaking, bone marrow failure is rare in this "sterile" inflammatory environment. Despite cytopenia, anemia, overproduction of myeloid cells, immunosenescence, other hematologic comorbidities, occurring in autoimmune diseases (eg: rheumatoid arthritis (RA), juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), colitis, etc.). 5. Aging is associated with chronic low-grade inflammation (i.e., a 2- to 4-fold increase in serum levels of IL-1, IL-6, TNF, and c-reactive protein), a state often referred to as inflammatory aging. This phenotype, observed in mice and humans, is attributed to cumulative lifetime exposure to infectious and non-infectious agents and/or senescence-associated cytokines, leading to a self-persistent, malignant pro-inflammatory cycle. Senescence is also associated with functional changes in mature and immature hematopoietic stem cells. Aging hematopoietic stem cells show increased pool size and quiescent state, decreased self-renewal ability, increased myeloid/megakaryocyte differentiation bias, increased DNA damage accumulation and proliferative stress markers, resistance to apoptosis, epigenetic and transcriptional alterations, loss of autophagy ability, decreased homing ability, and increased expression of adhesion molecules. Impaired neutrophil burial function and increased caspase-1 activity in elderly bone marrow macrophages were associated with increased IL-1β levels and enhanced differentiation bias of hematopoietic stem cell megakaryocytes (associated with CD41 and CD61 expression). Senescent bone marrow stromal cells show enhanced IL-6 and TGF-β signaling pathways. Inhibition of IL-6 improves erythrocyte progenitor cell function in aged mice, while TGF-β neutralization leads to reversal of age-related hematopoietic stem cell megakaryocyte differentiation bias, increases lymphoid progenitor cell production, and rebalances hematopoietic stem cell lineage output in transplantation assays. Plasma cells from aged mice accumulate in BM, and they are shown to increase TLR-driven activation and produce (along with stromal cells) a positive feedback network of pro-inflammatory cytokines, including IL-1, TNF-α, and M-CSF), promoting hematopoietic stem cell myeloid differentiation bias. Effect of inflammatory cytokines on hematopoiesis Type I interferon type I IFN inducers or IFN-α itself, achieved through IFN-α/β receptors IFNAR and STAT1, increasing the level of MYC protein and decreasing the expression of quiescent genes, can promote the proliferation of dormant hematopoietic stem cells. When hematopoietic stem cells remain quiescent, they are protected from the pro-apoptotic effects of p53-dependent type I IFNs. The effects of type I IFNs are negatively regulated by Irf2, a transcription factor-deficient hematopoietic stem cell that exhibits significant impaired function. Acute IFN-γ exposure to type II interferon, which drives hematopoietic cell proliferation through IFNGR and STAT1, and apoptosis mediated by Fas.
Chronic IFN-γ exposure (via chronic infection) leads to increased proliferative stress, which may be due to coverage of irgm1-dependent cell cycle and IFN response inhibition. Like type I interferons, IFN-γ initiates apoptosis of hematopoietic stem cells in response to secondary stress (in vitro culture). Impaired hematopoietic stem cell function has also been attributed to enhanced BATF2-dependent end-myeloid differentiation, which depletes the hematopoietic stem cell pool and severely impairs self-renewal capacity. Notably, the surface expression of IFNGR among hematopoietic stem cells was heterogeneous, and IFNGR+ hematopoietic stem cells exhibited myeloid bias and reduced regenerative activity. The role of TNF-αTNF-α in hematopoietic stem cell function is still an important area that requires further research. Acute TNF-α exposure leads to hematopoietic stem cell proliferation and transient activation of the typical NF-κB pathway, thereby maintaining the survival of hematopoietic stem cells during proliferation. Interestingly, after 48 h, initial TNF-α exposure no longer maintains NF-κB pathway activity, resulting in ripk3-mlkl-mediated necrosis, which is associated with reduced hematopoietic stem cell regeneration capacity. During chronic TNF-α in vitro exposure, sustained p65-NF-κB-mediated pro-survival signaling activity prevents necrosis and induces myeloid differentiation in blood stem cells by inducing Pu.1. This may further promote the reconstitution of hematopoietic stem cells at rest by inhibiting cell cycle activators, thereby protecting hematopoietic stem cells from necrosis while terminating the regenerative response. Therefore, TNF signaling may play different roles depending on the environment and dose. IL-1
Hematopoietic stem cells that are acutely exposed to IL-1β, by activating the transcription factor PU.1, exhibit MyD88-dependent proliferation and myeloid differentiation without losing their ability to self-renew. Short-term or low-dose IL-1α/IL-1β may prevent chemoradiotherapy-induced myelosuppression and protect cyclophosphamide-induced neutropenia mice from sepsis. Chronic IL-1β exposure, resulting in a reversible decrease in long-term revivalability in phenotypic SLAM hematopoietic stem cells. However, recent studies have shown that the long-term effects of chronic IL-1β exposure on hematopoietic stem cell reconstitution activity may actually be minimal.
G-CSF
Administration of G-CSF in vivo can lead to transient hematopoietic stem cell proliferation, peripheral mobilization, and expansion of the central region. However, long-term treatment of hematopoietic stem cells with G-CSF resulted in the overall loss of regenerative and self-renewal activity, which is associated with the enhanced TLR/MyD88 signaling pathway. Resources
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