Interleukin 1α and the inflammatory process

Abstract

Inflammation occurs after disruption of tissue homeostasis by cell stress, injury or infection and ultimately involves the recruitment and retention of cells of hematopoietic origin, which arrive at the affected sites to resolve damage and initiate repair. Interleukin 1α (IL-1α) and IL-1β are equally potent inflammatory cytokines that activate the inflammatory process, and their deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. Although much attention has been given to understanding the biogenesis of IL-1β, the biogenesis of IL-1α and its distinctive role in the inflammatory process remain poorly defined. In this review we examine key aspects of IL-1α biology and regulation and discuss its emerging importance in the initiation and maintenance of inflammation that underlie the pathology of many human diseases.

Figure 1

Molecular modifications of IL-1α that regulate its intracellular distribution and bioavailability. Constitutive or inducible expression of IL-1α produces full-length pro-IL-1α. After synthesis, pro-IL-1α is localized into the nucleus, cytosol or lysosomal compartment or is displayed on the outer leaflet of the plasma membrane. Intracellular localization of pro-IL-1α can change in response to specific stimuli and pro-IL-1α can also be cleaved by calpain to generate IL-1α-NTP and a mature C-terminal IL-1α form. Both IL-1α-NTP and pro-IL-1α possess a functional NLS signal and bind HAX1 to allow translocation into the nucleus. In the nucleus, IL-1α-NTP binds transcription regulation factors and activates expression of proinflammatory cytokines and chemokines independently of IL-1R1 signaling. Pro-IL-1α can bind chromatin, which allows sequestration of pro-IL-1α from the cytosol into the nucleus, thereby limiting aberrant IL-1α-dependent inflammation during apoptosis. In the cytosol, glycosylation of pro-IL-1α may allow pro-IL-1α translocation onto the outer surface of the cell. Plasma-membrane-bound pro-IL-1α can be released by mannose, suggesting a lectin-like mechanism of anchorage of pro-IL-1α to the outer leaflet of the plasma membrane. In the cytosol, pro-IL-1α can form a complex with inhibitory IL-1R2. Cytosolic pro-IL-1α can be polyubiquitinated, leading to its proteosomal degradation. Although several post-translational modifications of IL-1α-NTP and pro-IL-1α have been reported, formal confirmation of their functional importance is currently lacking.

Figure 2

Biological contexts of IL-1α-mediated signaling. (a) If a cell experiences supra-physiological stress that leads to necrosis, cytosolic pro-IL-1α is passively released through the ruptured plasma membrane and triggers the ‘alarm’ call, a functional IL-1R1-dependent proinflammatory response. Pro-IL-1α association with inhibitory IL-1R2 in the cytosol interferes with pro-IL-1 alarmin function. Inhibitory IL-1R2 association with pro-IL-1α can be relieved by capsase-1-dependent proteolysis of IL-1R2. In stimulated cells, pro-IL-1α is displayed on the cell surface. Plasma-membrane-bound pro-IL-1α is fully biologically active and can trigger local inflammatory responses from living cells. Membrane-bound pro-IL-1α can be cleaved extracellularly by granzyme B, chymase or elastase to produce a C-terminal mature IL-1α fragment that is also biologically active. (b) In hematopoietic cells, the proinflammatory stimuli that induce pro-IL-1β expression also activate expression of pro-IL-1α. However, pro-IL-1β is not biologically active and requires cleavage by capsase-1 in an inflammasome-dependent manner. This cleavage produces mature IL-1β and stimulates its secretion from the cell. Many pathogens express virulence factors that block caspase-1 activation and, therefore, maturation of pro-IL-1β and pyroptotic cell death. In these settings, pro-IL-1α can still be displayed at the cell surface and activate local IL-1R1-dependent inflammatory responses, thus bypassing blockade of IL-1β processing and release. Under the conditions of pyroptotic cell death, both pro-IL-1α and mature IL-1β are released to activate local and systemic inflammation.

Figure 3

IL-1α-driven inflammatory loop model. (a) IL-1α expression is induced in response to oxidative, genotoxic and metabolic stressors; hormonal stimulation; proinflammatory mediators that activate TNF-R1, IL-1R1 or TLR signaling; or infection. Without cell death, these stimuli trigger translocation of pro-IL-1α onto a plasma membrane and the appearance of membrane-bound pro-IL-1α, which activates IL-1R1-dependent chemokine and cytokine production from neighboring nonhematopoietic cells or tissue-resident macrophages. This initial IL-1α-dependent chemokine production leads to a recruitment of myeloid cells to the site of stress. Upon arrival, myeloid cells receive IL-1α-dependent IL-1R1 stimulation, which leads to the expression of pro-IL-1α and pro-IL-1β. Therefore, in the context of alive nonhematopoietic or residential hematopoietic cells under stress, IL-1α-initiated signaling triggers the recruitment of cells from hematopoietic compartment, which can amplify and sustain IL-1R1-dependent inflammation through the new round of IL-1α and IL-1β production, thus closing an inflammatory loop of IL-1-IL-1RI-signaling-dependent chemokine production and recruitment of inflammatory cells to the site of stress that now can be sustained only by cells of hematopoietic origin. (b) Upon necrotic cell death due to damage, stress or infection, the IL-1α-driven induction of the inflammatory loop is triggered by the passive release of pro-IL-1α into the surrounding milieu, where IL-1α functions as an alarmin. The pro-IL-1α released from necrotic cells activates IL-1R1 signaling on neighboring cells, leading to the recruitment of hematopoietic cells that can further sustain inflammation as in a.