Blocking IL-1 Signaling Improves Hematopoietic Function in Old Mice
Inflammatory signaling is made up of a broad range of different molecules, some of which are better studied than others. Chronic, unresolved inflammation increases with age and is disruptive to tissue structure and function. The research community spends more time investigating ways to interfere in this signaling (such as the TNF inhibitors used to treat autoimmune conditions) than it does in search of ways to prevent chronic inflammation from occurring in the first place (such as senolytic therapies to remove senescent cells and their pro-inflammatory secretions). This is unfortunate, as suppression of specific inflammatory signals affects both excess, unwanted inflammation and necessary, useful inflammation. The result may be a net improvement, considering the alternative of no treatment, but it is certainly the case that immune function is degraded in ways that negatively affect long-term health.
The aging of the immune system into a state of chronic inflammation is a feedback loop in which inflammation produces further disruption of immune function by affecting processes and organs involved in the creation of immune cells. Atrophy of the thymus is accelerated by chronic inflammation, and so is the decline and altered function of hematopoietic stem cell populations in the bone marrow. Hematopoietic cell populations reside in niche structures, and these niches suffer as chronic inflammation ramps up with age. In today's open access paper, researchers quantify the contribution of one specific inflammatory signal molecule to this aspect of aging, and demonstrate that inhibition helps to slow down the loss of function.
Chronic inflammation is a hallmark of ageing, but its consequences for tissue function remain unclear. Here we demonstrated that bone marrow ageing is defined by niche remodelling, increased IL-1β production by dysfunctional stromal cells and activation of inflammatory response programmes in both haematopoietic and niche cells. This chronic, low-grade inflammation directly contributes to the loss of endosteal mesenchymal populations, impaired osteogenesis and vascular dysfunction. These changes, alongside expanded inflammatory LepR+ MSC cells, drive lineage biases and regenerative defects from the old blood system. Niche inflammation also activates emergency myelopoiesis pathways in hematopoietic cells, reinforcing myeloid cell production at the expense of lymphoid and erythroid commitment. This blunts regenerative responses that rely on acute activation of these pathways, which then cause exacerbated phenotypes following stress in old mice.
A reduction in endosteal niches and expansion of neurovascular central marrow niches that promote megakaryopoiesis through increased production of pro-inflammatory cytokines, including IL-6 and IL-1β, has been previously described. In addition, a role for IL-1β produced by aged macrophages has been implicated in promoting megakaryopoiesis, and for IL-1β produced by myeloid cells in response to the ageing microbiome in promoting myelopoiesis. Here we showed that chronic IL-1β production by endosteal stromal cells acts in trans to induce inflammatory remodelling of marrow LepR+ MSC cells and contributes to many aspects of altered blood production with age, in particular chronic engagement of emergency myelopoiesis. Conversely, blocking IL-1 signalling attenuates central marrow LepR+ MSC niche inflammation and dampens hematopoietic stem cell activation, recovering some differentiation biases and improving acute regenerative potential. We also found that blocking TNFα, another candidate mediator of these effects, did not prevent niche or blood ageing, which highlights the central role of IL-1.
Our findings add to the growing body of evidence for microenvironmental inflammation in driving blood ageing and the specific importance of IL-1β as a driver of this process. They establish IL-1 as a central factor that damages the crosstalk between the bone marrow niche and the blood system, with inflammatory remodelling of the central marrow probably having deleterious consequences for innervation and vascular function. Consistently, IL-1β levels correlated with age-related mortality in human studies. They indicate a potential application of IL-1 inhibitors to improve blood production in the elderly, especially in regenerative settings following chemotherapy or immunosuppression.