Figure 1.
IL-1α/β signaling pathway as a driver of inflammaging. Left panel depicts the IL-1α/β signaling pathway: IL-1α is produced as a precursor protein (pro–IL-1α), which is constitutively expressed in multiple cell types (eg, keratinocytes, fibroblasts, and endothelial and epithelial cells) and shuttles between cytoplasm and nucleus, in which it acts as a transcription factor, functionally implicated in proliferation, senescence, and apoptosis. Upon cellular necrosis, cytoplasmatic pro–IL-1α is released together with cell contents acting as an “alarmin” in surrounding cells. Under inflammatory conditions, pro–IL-1α is cleaved into mature IL-1α that signals either as an extracellular or as a membrane bound molecule. IL-1β is primarily produced by myeloid cells in a precursor form. Upon danger/pathogen-associated molecular pattern (D/PAMP) recognition by pattern recognition receptors and downstream inflammasome-mediated proteolytic activation, pro-IL-1β matures into IL-1β. Secretion of IL-1β can occur via active secretion or via increased cellular permeability once cells go into pyroptosis. IL-1 engagement with IL-1R1/3 leads to downstream pathway activation, which can be prevented by naturally occurring inhibitors like soluble IL-1R1 antagonist (IL-1RN) and antagonistic receptor (IL-1R2, which lacks an intracellular signaling domain). IL-1 pathway inhibiting drugs are depicted. Recombinant human IL-1Ra (anakinra) targets both IL-1α and IL-1β, as does the soluble IL-1R (rilonacept). Neutralizing antibodies selectively target IL-1α (bermekimab) or IL-1β (canakinumab). General and cell-type specific effects of IL-1 signaling pathway activation are indicated. IL-1 pathway targeting compounds are indicated. Right panel depicts the interplay between aging, inflammaging and IL-1 signaling in the BM. Age associated molecular alterations result in the indicated cellular dysfunctions, which converge in inducing inflammaging. Inflammaging leads to multiple tissue alterations that result in D/PAMP production. D/PAMPs are sensed in the BM by myeloid, plasma, and stromal cells leading to increased IL-1 production, which, in turn, is sensed by niche cells and HSCs, triggering niche degradation and myelopoiesis, respectively. This cycle amplifies the local amounts of IL-1, leading in the long term to increased inflammatory burden, further amplifying the initial inflammaging levels.

IL-1α/β signaling pathway as a driver of inflammaging. Left panel depicts the IL-1α/β signaling pathway: IL-1α is produced as a precursor protein (pro–IL-1α), which is constitutively expressed in multiple cell types (eg, keratinocytes, fibroblasts, and endothelial and epithelial cells) and shuttles between cytoplasm and nucleus, in which it acts as a transcription factor, functionally implicated in proliferation, senescence, and apoptosis. Upon cellular necrosis, cytoplasmatic pro–IL-1α is released together with cell contents acting as an “alarmin” in surrounding cells. Under inflammatory conditions, pro–IL-1α is cleaved into mature IL-1α that signals either as an extracellular or as a membrane bound molecule. IL-1β is primarily produced by myeloid cells in a precursor form. Upon danger/pathogen-associated molecular pattern (D/PAMP) recognition by pattern recognition receptors and downstream inflammasome-mediated proteolytic activation, pro-IL-1β matures into IL-1β. Secretion of IL-1β can occur via active secretion or via increased cellular permeability once cells go into pyroptosis. IL-1 engagement with IL-1R1/3 leads to downstream pathway activation, which can be prevented by naturally occurring inhibitors like soluble IL-1R1 antagonist (IL-1RN) and antagonistic receptor (IL-1R2, which lacks an intracellular signaling domain). IL-1 pathway inhibiting drugs are depicted. Recombinant human IL-1Ra (anakinra) targets both IL-1α and IL-1β, as does the soluble IL-1R (rilonacept). Neutralizing antibodies selectively target IL-1α (bermekimab) or IL-1β (canakinumab). General and cell-type specific effects of IL-1 signaling pathway activation are indicated. IL-1 pathway targeting compounds are indicated. Right panel depicts the interplay between aging, inflammaging and IL-1 signaling in the BM. Age associated molecular alterations result in the indicated cellular dysfunctions, which converge in inducing inflammaging. Inflammaging leads to multiple tissue alterations that result in D/PAMP production. D/PAMPs are sensed in the BM by myeloid, plasma, and stromal cells leading to increased IL-1 production, which, in turn, is sensed by niche cells and HSCs, triggering niche degradation and myelopoiesis, respectively. This cycle amplifies the local amounts of IL-1, leading in the long term to increased inflammatory burden, further amplifying the initial inflammaging levels.

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