Enhanced Pro-Inflammatory Response of Macrophages to Interleukin-33 in an Allergic Environment

Abstract

Background: Allergic asthma is common in childhood and is associated with a T-helper type 2 (Th2)-biased immunological response. Exacerbations of asthma are characterised by increased inflammation of the airways, which appears to be driven by interleukin (IL)-33 that can activate pulmonary macrophages. The Th2 cytokine environment of allergic asthma may contribute to exaggerated airway inflammation. Objectives: To test this, we assessed whether production of pro-inflammatory cytokines by IL-33-stimulated macrophages was enhanced in cells pre-treated with the key Th2 cytokines IL-4 and IL-13. We also investigated whether this was associated with altered expression of regulatory microRNAs (miRNAs). Methods: RAW264.7 cells cultured with IL-4 and IL-13 for 48 h were stimulated with IL-33 for 4 h. Pro-inflammatory mediators were assessed using quantitative real-time PCR (RT-PCR). Expression of miRNAs was assessed using microarrays and RT-PCR. In further experiments, we examined whether resolvin E1 (RvE1), which promotes the resolution of experimental asthmatic inflammation in vivo, could suppress the enhanced response by treating cells with RvE1 concurrently with IL-33 stimulation. Results: In cells pre-treated with IL-4 and IL-13, expression of mRNA for Ccl3, Ccl5, Ccl17, Ccl24, and Il1b in response to IL-33 stimulation was significantly increased. This was paralleled by up-regulated expression of miR-155-5p, a miRNA that is predicted to regulate several aspects of allergic inflammation. RvE1 suppressed the enhanced production of Ccl3, Ccl5, Ccl24, and Il1b. Conclusions: We conclude that IL-33-activated macrophages may contribute to the exaggerated airway inflammation in exacerbations of allergic asthma, and that RvE1 has potential as a therapeutic agent that targets macrophages.

IL-33–Stimulated Murine Mast Cells Polarize Alternatively Activated Macrophages, Which Suppress T Cells That Mediate Experimental Autoimmune Encephalomyelitis

“…However, we failed to detect IL-13 production by IL-33-stimulated macrophages. Consistent with our findings, a number of other studies also showed that IL-33 cannot directly polarize AAMF in vitro (26,34,37,49); however, these studies did demonstrate that IL-33 could enhance the responsiveness of macrophages to IL-4 or IL-13. This suggests that IL-4/IL-13-stimulated AAMF can directly respond to IL-33 without the need for a third-party cell.…”

Alarmins and MicroRNAs, a New Axis in the Genesis of Respiratory Diseases: Possible Therapeutic Implications

“…Evidence suggests that a relevant role is played by alarmins and miRNAs in the determinism of respiratory diseases. IL-33 and HMGB1 have a significant role in Th2 inflammation and severe asthma [ 56 , 61 ]. In addition, alarmin levels correlate negatively with pulmonary function [ 62 , 63 ] and promote the remodelling of airways and exacerbation of disease [ 77 ].…”

“…Chia et al observed an increase in IL-33 associated with an increase in miR-155 in macrophages cultured with IL-4 and IL-13. Future studies are necessary to clarify the link between alarmin and miR-155 [ 56 ].…”

“…In RAW264.7 cells treated with IL-4 and IL-13, the gene expression of Ccl3, Ccl5, Ccl17, Ccl24, and Il1b after IL-33 activation was increased; this was equivalent to the increased expression of miRNA-155-5p, an miRNA that is expected to control the onset of allergic inflammation. Resolvin (RvE1), a substance that can improve asthmatic inflammation in vivo, reduced the increased generation of Ccl3 , Ccl5 , Ccl24 , and Il1b [ 56 ]. Therefore, IL-33-stimulated macrophages may participate in airway inflammation and the aggravation of allergic asthma, while RvE1 might operate as a factor that targets macrophages [ 57 , 58 ].…”

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

“…The RvE1 receptor, CMKLR1, is expressed on NK cells, where its activation leads to NK cell attraction and activation that resolves lung inflammation [ 72 ]. However, by acting to dampen macrophage/neutrophil/mast cell activation, RvD1 and RvE1 also decrease the chemoattraction and activation of NK cells and CD8+ T cells, under some experimental conditions [ 73 ]. The temporal regulation of SPMs across different immune cells over the course of SARS-CoV-2 infection will be important to determine.…”