Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality worldwide that is associated with advanced atherosclerosis. Inflammatory cytokines synthesized by both resident vascular cells and bone marrow-derived macrophages, are recognized as key mediators in the chronic inflammatory environment that is typical of atherosclerosis [1], [2], [3]. IL-1α and IL-1β, the main members of the IL-1 family of cytokines, promote the expression of a collection of inflammatory genes in the arterial wall. The IL-1α and IL-1β agonists as well as IL-1Ra, the specific receptor antagonist, all work through binding to IL-1 receptor type 1 (IL-1R1) [4], [5]. IL-1α and IL-1β are produced as precursors and are processed to mature proteins by specific cellular proteases. IL-1β is only active as a mature secreted molecule after being cleaved by caspase-1, while IL-1α is active both in the mature and the precursor forms when bound to IL-1R1. Non-immune cells constitutively express IL-1α at low levels, while macrophages are stimulated to produce IL-1α by danger- and pathogen-associated molecular patterns, such as Lipopolysaccharides (LPS) [4], [6], [7]. After an apoptotic stimulus, IL-1α translocates to the nucleus, binds to chromatin and is retained in the cell [8]. However, when the cell becomes necrotic, IL-1α is released and can serve as a danger signal that induces recruitment of inflammatory cells to promote sterile inflammation [6], [9], [10]. IL-1α can be secreted either by a regulated process that depends on the inflammasome and caspase-1, or in an unregulated manner [9], [11], [12], [13]. Preclinical experiments showed that unopposed IL-1 signaling promoted atherogenesis [14], [15], and IL-1Ra overexpression or lack of IL-1β, decreased early atherosclerosis development in mice [16], [17], [18], [19]. However, these reports did not study the role of IL-1α nor identified the cell type from which IL-1 promoted atherogenesis. Data from our group, which was confirmed later by Freigang et al., demonstrated that IL-1α from cells originating in the bone marrow is critical for atherogenesis [4], [7], [9]. We also showed that IL-1R1 in vascular cells mediated the atherogenic effects of IL-1 in apoE-deficient mice [5]. Collectively, these studies suggest that IL-1α from bone marrow-derived cells promotes early atherosclerosis by binding to IL-1 receptor on vascular wall cells. However, the role of IL-1α in progression to more advanced atherosclerosis is less clear [20], [21].

The unfolded protein response (UPR) is a part of the endoplasmic reticulum (ER) stress response where it functions in maintaining the secretory pathway homeostasis by promoting the protein folding milieu in the ER [22]. Persistent ER stress may lead to UPR failure and consequently to apoptotic cell death. This process is mediated by reactive oxygen species, calcium perturbations, and the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) [23]. CHOP is a central constituent in apoptosis mediated by ER stress both in hepatocytes and macrophages [24], [25], [26], [27]. We previously showed that IL-1α is required in ER stress-induced activation of inflammatory cytokines in hepatocytes and in the associated induction of steatohepatitis [28]. Given the importance of ER stress-mediated CHOP induction in progression to advanced atherosclerosis [29], we hypothesized that IL-1α participates in ER stress-induced inflammation and CHOP induction. Here we show that ER stress induction in macrophages results in the specific production and secretion of IL-1α and not IL-1β, and that IL-1α is required in ER stress-induced production of CHOP. We further demonstrate that this IL-1α-dependent CHOP production is specifically mediated through the PERK-ATF4 signaling pathway. Altogether, these findings point to IL-1α as a central mediator in ER stress-related inflammation and apoptosis in macrophages, and highlights it as a putative target in novel strategies for prevention and treatment of ASCVD.