Altered microRNA expression links IL6 and TNF-induced inflammaging with myeloid malignancy in humans and mice

Abstract

Aging is associated with significant changes in the hematopoietic system, including increased inflammation, impaired hematopoietic stem cell (HSC) function, and increased incidence of myeloid malignancy. Inflammation of aging (“inflammaging”) has been proposed as a driver of age-related changes in HSC function and myeloid malignancy, but mechanisms linking these phenomena remain poorly defined. We identified loss of miR-146a as driving aging-associated inflammation in AML patients. miR-146a expression declined in old wild-type mice, and loss of miR-146a promoted premature HSC aging and inflammation in young miR-146a–null mice, preceding development of aging-associated myeloid malignancy. Using single-cell assays of HSC quiescence, stemness, differentiation potential, and epigenetic state to probe HSC function and population structure, we found that loss of miR-146a depleted a subpopulation of primitive, quiescent HSCs. DNA methylation and transcriptome profiling implicated NF-κB, IL6, and TNF as potential drivers of HSC dysfunction, activating an inflammatory signaling relay promoting IL6 and TNF secretion from mature miR-146a−/− myeloid and lymphoid cells. Reducing inflammation by targeting Il6 or Tnf was sufficient to restore single-cell measures of miR-146a−/− HSC function and subpopulation structure and reduced the incidence of hematological malignancy in miR-146a−/− mice. miR-146a−/− HSCs exhibited enhanced sensitivity to IL6 stimulation, indicating that loss of miR-146a affects HSC function via both cell-extrinsic inflammatory signals and increased cell-intrinsic sensitivity to inflammation. Thus, loss of miR-146a regulates cell-extrinsic and -intrinsic mechanisms linking HSC inflammaging to the development of myeloid malignancy.

Decreased serum levels of inflammaging marker miR-146a are associated with clinical response to tocilizumab in COVID-19 patients

“…Notably, circulating miR-146a levels significantly decline with age and chronic age-related diseases and conditions, such as type 2 diabetes and frailty (Mensà et al, 2019; Ong et al, 2019). Current literature agrees about its pivotal role in inflammaging and age-related diseases (Grants et al, 2020). We recently suggested that the features of the current pandemic strongly suggest a role of inflammaging in worse COVID-19 outcomes, which mainly affect old people affected by age-related diseases (Bonafè et al, 2020; Storci et al, 2020).…”

“…The pivotal role of miR-146a-5p has been reported in a number of cell types that orchestrate the inflammatory response, including endothelial cells (Mensà et al, 2019; Olivieri et al, 2013a), microglial cells (Liu et al, 2020b), monocytes and macrophages, (Li et al, 2015; Zhou et al, 2019), and adipocytes (Roos et al, 2016). Recently, a reduced expression of miR-146a-5p was observed in a subgroup of patients affected by acute myeloid leukemia with inflammaging and poor outcome (Grants et al, 2020). Therefore, on the basis of the current literature, a decline in miR-146a-5p levels would be expected to unleash the release of inflammatory cytokines, e.g.…”

Ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of IL-6

“…These features are also observed in aged wild-type mice and are associated with a skewing towards the myeloid lineage and a reduced proliferative capacity of HSCs 50 , 51 . Loss of microRNA-146a (miR-146a) in HSCs with ageing also promotes a myeloid bias 52 . Furthermore, myeloid cells derived from miR-146a-deficient HSCs have elevated levels of both IL-6 and tumour necrosis factor (TNF) 52 , which connects altered regulation of transcription in HSCs to inflammation.…”

“…Loss of microRNA-146a (miR-146a) in HSCs with ageing also promotes a myeloid bias 52 . Furthermore, myeloid cells derived from miR-146a-deficient HSCs have elevated levels of both IL-6 and tumour necrosis factor (TNF) 52 , which connects altered regulation of transcription in HSCs to inflammation. Overall, these studies indicate that ageing has effects on HSCs via several complex pathways that lead to reduced HSC function.…”

EnvIRONmental Aspects in Myelodysplastic Syndrome

“…Inflammation is an increasingly accepted feature of MDS [ 102 , 103 , 104 ]. Different aspects of inflammation and associated dysregulated chronic immune responses have been found to play a role (age-related inflammation, disease-associated intrinsic and extrinsic inflammation).…”