IL-1α and IL-1β Recruit Different Myeloid Cells and Promote Different Stages of Sterile Inflammation

Abstract

The immune system has evolved to protect the host from invading pathogens and to maintain tissue homeostasis. Although the inflammatory process involving pathogens is well documented, the intrinsic compounds that initiate sterile inflammation and how its progression is mediated are still not clear. Because tissue injury is usually associated with ischemia and the accompanied hypoxia, the microenvironment of various pathologies involves anaerobic metabolites and products of necrotic cells. In the current study, we assessed in a comparative manner the role of IL-1α and IL-1β in the initiation and propagation of sterile inflammation induced by products of hypoxic cells. We found that following hypoxia, the precursor form of IL-1α, and not IL-1β, is upregulated and subsequently released from dying cells. Using an inflammation-monitoring system consisting of Matrigel mixed with supernatants of hypoxic cells, we noted accumulation of IL-1α in the initial phase, which correlated with the infiltration of neutrophils, and the expression of IL-1β correlated with later migration of macrophages. In addition, we were able to show that IL-1 molecules from cells transfected with either precursor IL-1α or mature IL-1β can recruit neutrophils or macrophages, respectively. Taken together, these data suggest that IL-1α, released from dying cells, initiates sterile inflammation by inducing recruitment of neutrophils, whereas IL-1β promotes the recruitment and retention of macrophages. Overall, our data provide new insight into the biology of IL-1 molecules as well as on the regulation of sterile inflammation.

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

“…The most notable changes in the cells treated with the combination of LG268 and LPS compared with LPS alone were a 3-fold downregulation of CSF3 and a 2.5-fold decrease of CXCL2 and IL1b mRNA expression. These cytokines play important roles in inflammation: CSF3 in the production and function of granulocytes (30), CXCL2 in the recruitment of neutrophils (31), and IL1b in promoting the infiltration of inflammatory myeloid cells and in angiogenesis (32,33). A complete list of the inflammatory cytokines, chemokines, and their receptors that showed any detectable changes in the panel of 440 genes following treatment with LG268 are listed in Supplementary Table S1.…”

Secreted IL‐1α promotes T‐cell activation and expansion of CD11b+Gr1+ cells in carbon tetrachloride‐induced liver injury in mice

“…IL-1α and IL-1β can function through the same IL-1 receptor. However, they may play different roles by recruiting different myeloid cells during different stages of sterile inflammation [42]. Inflammasomes and caspase-1 activity are required for the maturation and secretion of IL-1β.…”

“…IL-1α is present in the nucleus, cytosol, or cell membrane, and can be released from the necrotic cells to induce inflammation [41,42]. IL-1α and IL-1β can function through the same IL-1 receptor.…”

“…IL-1α is defined as an "alarm cytokine" that can initiate inflammatory responses by inducing a cascade of other proinflammatory genes [40]. IL-1α is present in the nucleus, cytosol, or cell membrane, and can be released from the necrotic cells to induce inflammation [41,42]. IL-1α and IL-1β can function through the same IL-1 receptor.…”

IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G

“…Further analyses revealed that IL-33 is constitutively expressed to high levels in the nuclei of endothelial and epithelial cells in vivo (27) and that it can be released in the extracellular space after cellular damage (23,24). IL-33 was, thus, proposed (23,24,27) to function as an endogenous danger signal or alarmin, similar to IL-1α and high-mobility group box 1 protein (HMGB1) (28)(29)(30)(31)(32), to alert cells of the innate immune system of tissue damage during trauma or infection.…”