Abstract
Production and activity of interleukin (IL)-1β are kept under strict control in our body, because of its powerful inflammation-promoting capacity. Control of IL-1β production and activity allows IL-1 to exert its defensive activities without causing extensive tissue damage. Monocytes are the major producers of IL-1β during inflammation, but they are also able to produce significant amounts of IL-1 inhibitors such as IL-1Ra and the soluble form of the decoy receptor IL-1R2, in an auto-regulatory feedback loop. Here, we investigated how innate immune memory could modulate production and activity of IL-1β by human primary monocytes and monocyte-derived tissue-like/deactivated macrophages in vitro. Cells were exposed to Gram-negative (Escherichia coli) and Gram-positive (Lactobacillus acidophilus) bacteria for 24 h, then allowed to rest, and then re-challenged with the same stimuli. The presence of biologically active IL-1β in cell supernatants was calculated as the ratio between free IL-1β (i.e., the cytokine that is not bound/inhibited by sIL-1R2) and its receptor antagonist IL-1Ra. As expected, we observed that the responsiveness of tissue-like/deactivated macrophages to bacterial stimuli was lower than that of monocytes. After resting and re-stimulation, a memory effect was evident for the production of inflammatory cytokines, whereas production of alarm signals (chemokines) was minimally affected. We observed a high variability in the innate memory response among individual donors. This is expected since innate memory largely depends on the previous history of exposure or infections, which is different in different subjects. Overall, innate memory appeared to limit the amount of active IL-1β produced by macrophages in response to a bacterial challenge, while enhancing the responsiveness of monocytes. The functional re-programming of mononuclear phagocytes through modulation of innate memory may provide innovative approaches in the management of inflammatory diseases, as well as in the design of new immunization strategies. In this respect, the interindividual variability in innate memory suggests the need of a personalized assessment.
Highlights
During the last several years, our knowledge on the interleukin (IL)-1 family molecules, as central mediators of innate immunity/inflammation and as “guilty” molecules of the development of autoinflammatory, autoimmune, infectious and degenerative diseases, has increased (Sims and Smith, 2010; Dinarello, 2011a,b, 2013; Dinarello and van der Meer, 2013; Garlanda et al, 2013a) The IL-1 family encompasses 11 cytokines/ligands and 10 related receptors (Dinarello et al, 2010; Boraschi and Tagliabue, 2013)
Our study focuses on changes in the levels of active available IL-1β produced by cells exposed and re-stimulated with Gram-positive and Gramnegative bacteria and bacterial components
In the case of CCL2, the donor-to-donor variation in the monocyte response was evident, with a decrease of production observed in response to LPS, and little/no variation, or a significant increase (L. acidophilus in donor 2) in other cases
Summary
During the last several years, our knowledge on the interleukin (IL)-1 family molecules, as central mediators of innate immunity/inflammation and as “guilty” molecules of the development of autoinflammatory, autoimmune, infectious and degenerative diseases, has increased (Sims and Smith, 2010; Dinarello, 2011a,b, 2013; Dinarello and van der Meer, 2013; Garlanda et al, 2013a) The IL-1 family encompasses 11 cytokines/ligands and 10 related receptors (Dinarello et al, 2010; Boraschi and Tagliabue, 2013). The IL-1-induced inflammation is regulated by a complex interaction of receptors and soluble inhibitors, whose concerted action determines the timing of activity and its shut-off. Both IL-1α and IL-1β bind to IL-1R1 and form an activating complex with the signaling chain IL-1R3. The receptor antagonist IL-1Ra binds to IL-1R1 receptor with high affinity, thereby competing with IL-1α and IL-1β, and does not recruit IL-1R3 ( the complex is inactive). The soluble forms of these receptors (sIL-1R1, sIL-1R2, sIL-1R3) have an inhibitory function by acting as ligand traps, and ensure a balance between amplification/activation of defensive responses and uncontrolled inflammation (Boraschi and Tagliabue, 2013; Garlanda et al, 2013b)
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