Alternative Pathways of IL-1 Activation, and Its Role in Health and Disease

Abstract

Cytokines activate or inhibit immune cell behavior and are thus integral to all immune responses. IL-1α and IL-1β are powerful apical cytokines that instigate multiple downstream processes to affect both innate and adaptive immunity. Multiple studies show that IL-1β is typically activated in macrophages after inflammasome sensing of infection or danger, leading to caspase-1 processing of IL-1β and its release. However, many alternative mechanisms activate IL-1α and IL-1β in atypical cell types, and IL-1 function is also important for homeostatic processes that maintain a physiological state. This review focuses on the less studied, yet arguably more interesting biology of IL-1. We detail the production by, and effects of IL-1 on specific innate and adaptive immune cells, report how IL-1 is required for barrier function at multiple sites, and discuss how perturbation of IL-1 pathways can drive disease. Thus, although IL-1 is primarily studied for driving inflammation after release from macrophages, it is clear that it has a multifaceted role that extends far beyond this, with various unconventional effects of IL-1 vital for health. However, much is still unknown, and a detailed understanding of cell-type and context-dependent actions of IL-1 is required to truly understand this enigmatic cytokine, and safely deploy therapeutics for the betterment of human health.

Inhibitory Effect of Catechin-Rich Açaí Seed Extract on LPS-Stimulated RAW 264.7 Cells and Carrageenan-Induced Paw Edema

“…The IL-1β is typically activated in macrophages after inflammasome sensing of infection or danger, leading to caspase-1 processing and driving inflammation after the release from macrophages [46]. The TLR4 receptor in monocytes and macrophages, when activated by LPS, induces IL-12 production and stimulates macrophages to produce other pro-inflammatory cytokines, driving inflammation [47].…”

Inflammasomes in Alveolar Bone Loss

“…Unlike TNF-α, IFNs, and IL-6, pro-IL-1β contains no N-terminal signal peptide for secretion and must be processed into its mature form, IL-1β. Although mast cell chymase and neutrophil proteinase 3 may also cleave IL-1β, this process is mainly regulated by inflammasome activation, as stated above ( 98 , 99 ). IL-1β promotes osteoclast differentiation both directly and indirectly ( 100 ).…”

“…NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) infected with P. gingivalis or treated with zoledronic acid increases IL-1β production ( 126 , 127 ). The released IL-1β and IL-18 can then recruit more macrophages to phagocytose cell debris and kill pathogens by enhancing phagosome acidification, thereby amplifying inflammatory responses and bone resorption ( 99 ). In addition to these bone-resident macrophages that may first sense most danger-related stimuli in the local environment, macrophages derived from circulating mononuclear cells may also be recruited to infected bone tissue ( 128 ).…”

Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome

“…Nteeba et al 2013). As a result, the increased levels of IL-1β at 16 wk HFD confirm the existence of alternative pathways to NLRP3 inflammasome, mediating IL-1β upregulation (Donado et al 2020;Jain et al 2020;Pyrillou, Burzynski, and Clarke 2020;Schmidt and Lenz 2012;Zhu and Kanneganti 2017). To this extent, we have recently shown the temporal pattern of expression of proinflammatory genes in CCs from DIO mice (Wołodko et al 2020).…”