Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF

Abstract

Inflammatory signals arising from the microenvironment have emerged as critical regulators of hematopoietic stem cell (HSC) function during diverse processes including embryonic development, infectious diseases, and myelosuppressive injuries caused by irradiation and chemotherapy. However, the contributions of cellular subsets within the microenvironment that elicit niche-driven inflammation remain poorly understood. Here, we identify endothelial cells as a crucial component in driving bone marrow (BM) inflammation and HSC dysfunction observed following myelosuppression. We demonstrate that sustained activation of endothelial MAPK causes NF-κB-dependent inflammatory stress response within the BM, leading to significant HSC dysfunction including loss of engraftment ability and a myeloid-biased output. These phenotypes are resolved upon inhibition of endothelial NF-κB signaling. We identify SCGF as a niche-derived factor that suppresses BM inflammation and enhances hematopoietic recovery following myelosuppression. Our findings demonstrate that chronic endothelial inflammation adversely impacts niche activity and HSC function which is reversible upon suppression of inflammation.

Obesity-induced inflammation: The impact of the hematopoietic stem cell niche

“…Additionally, LPS and TNF-α induce expression of Jagged-2 on BMECs and Notch-1 and -2 on hematopoietic cells, suggesting that these pathways may work together to promote Notch signaling in the BM during inflammation ( 115 ). Chronic activation of the inflammatory stress–associated MAPK pathway in BMECs ( 116 , 117 ) promotes aberrant NF-κB signaling, which is believed to drive myeloid bias in HSCs ex vivo at the expense of self-renewal ( 118 ). While the majority of this research has been within the context of acute infection and the associated immune response, several cytokine and signaling pathways (IL-1β, TNF-α, and TLR4) and the skewing toward myelopoiesis are also implicated in obesity, making these pathways prime targets for further analysis.…”

Implication of dietary phenolic acids on inflammation in cardiovascular disease

“…Diverse mechanisms are implicated in regulating immune and inflammatory responses relating to CVD. This includes signalling pathways such as the mitogen-activated protein kinases (MAPK) pathway Ramalingam et al, 2020), janus kinase/signal transducers/activators of the transcription (JAK/STAT) pathway (Shen et al, 2020;Ye et al, 2020) and the NF-κB pathway (Gao et al, 2020;Manjunatha et al, 2020). Among all of these, the NF-κB transcription factor seems to be the key player in the regulation of the CVD-related inflammatory response (Choy et al, 2019) where its activation may directly promote the production of cytokines (IL-1β, IL-6, TNF-α) and chemokines (MCP-1, MIP-1, CXC, CXCL10), besides promoting adhesion molecules (ICAM-1.…”

Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms

“…NFκB activation in hematopoietic niche cells is likely to severely affect hematopoiesis. This hypothesis is supported by a recent study which used an inducible endothelial-specific expression system to produce constitutive MAP kinase signaling in endothelial cells, downstream of an introduced phosphorylation-mimic MAPKK1 S218D, S222D ( 127 ). This produced secondary NFκB signaling hyperactivation in the bone marrow endothelial cells (plausibly a cell-autonomous effect), and the hematopoietic phenotype of HSC depletion by induction of proliferation and differentiation of HSC to myeloid progenitors, and consequent preferential production of myeloid cells in the setting of overall pancytopenia ( Figure 7A ).…”

“…It also resembles mouse phenotypes obtained when A20/TNFAIP3, an inhibitor of NFκB signaling activation by activated TNFR1, TLRs, and other signaling receptors, was eliminated ( 131 – 134 ). Furthermore, the hematopoietic phenotype induced by endothelial MAP kinase pathway hyperactivation was completely suppressed by introduction of IκBα (NFKBIA) S32A, S36A “super repressor”, which constitutively inhibits canonical NFκB signaling, exclusively in the endothelial cells ( 127 ). The implication is that NFκB hyperactivation in bone marrow endothelial cells, derived secondarily to MAP kinase pathway hyperactivation, was transmitted non-cell-autonomously to the hematopoietic compartment, resulting in NFκB-hyperactivated hematopoiesis.…”