Letter by Nagareddy et al Regarding the Article “Interleukin-1α (IL-1α) is a Central Regulator of Leukocyte-Endothelial Adhesion in Myocardial Infarction and in Chronic Kidney Disease”

To the Editor:

The cytokines of interleukin (IL)-1 family are involved in the development of atherosclerosis and its downstream pathologies including myocardial infarction (MI). However, the role of IL-1α is less widely studied compared to its homolog, IL-1β. We read with great interest the article by Schunk, et al¹ regarding the novel role of monocyte-derived IL-1α in promoting greater inflammation in AMI and CKD. The major premise for this study is that monocyte-derived IL-1α and its subsequent interaction with IL1RI on endothelial cells promote leukocyte-endothelial adhesion, thus aggravating vascular inflammation and leukocyte recruitment.

The observation that the absence of IL-1α completely prevented LPS-induced leukocyte-endothelial adhesion in dorsal skinfold chamber experiments is intriguing. LPS and many other TLR4 ligands applied directly to endothelial cells have shown to induce expression of multiple adhesion molecules (including Vcam1) via NF-κB signaling². These observations stand in odds with authors reasoning that these interactions are driven primarily by IL-1α derived from monocytes. Furthermore, these findings should be discussed in the context of TNFα, whose expression levels are generally elevated in inflammatory conditions such an atherosclerosis and MI. Since the authors found no impact of IL-1α-IL1R1 blockade on TNFα-stimulated monocyte-endothelial adhesion, this points to a significant contribution of TNFα-dependent and IL-1α-IL1R1-independent pathways in leukocyte binding.

IL-1α in addition to activating endothelial cells may have an extensive role in promoting systemic inflammation. Previous studies have demonstrated that IL-1β, another member of IL1 family induce myelopoiesis and amplify systemic inflammation post-MI in a IL1R1-dependent manner³. Unlike IL-1β, the circulating levels of IL-1α increases post ischemia-reperfusion injury⁴ and may induce myelopoiesis resulting in greater number of circulating monocytes and neutrophils⁵. Thus, a decrease in the number of myocardium-infiltrating F4/80 macrophages and Ly6G⁺ neutrophils in Il1a^−/− mice post-MI could be a consequence of suppressed myelopoiesis. Furthermore, ascribing a predominant and rather an exclusive role for monocytes in IL-1α production without cell-to-cell comparative studies may lead to false conclusions. Neutrophils being the first cells to arrive at the sites of sterile injury harbor a plethora of alarmin molecules including IL-1α and S100 calcium binding proteins (e.g. S100A8/A9). Identifying the predominant source of IL-1α would also be crucial in defining the most effective time window for intervention and, to prevent unintended effects of IL-1α suppression (for example delaying the activation of reparative phase).