IL-1 Receptor Regulates microRNA-135b Expression in a Negative Feedback Mechanism during Cigarette Smoke–Induced Inflammation

Abstract

Although microRNA-135b (miR-135b) is known to be associated with cancer, with recent work showing that it is massively induced in the pulmonary tissues of mice challenged with nanoparticles suggests a critical role for this microRNA in mediating inflammatory response. In this study, we investigated the expression and function of miR-135b in mice exposed to cigarette smoke or nontypeable Haemophilus influenzae (NTHi). Exposure to both cigarette smoke and NTHi elicited robust lung inflammation, but increased miR-135b expression was observed only in the lungs of cigarette smoke–exposed mice. Using IL-1R 1 knockout mice, we show that miR-135b expression is IL-1R1 dependent. A series of in vitro experiments confirmed the role of IL-1R1 in regulating miR-135b expression. In vitro activation of the IL-1R1 pathway in mouse embryonic fibroblast (NIH3T3) and lung epithelial (FE1) cells resulted in increased miR-135b, which was blocked by IL-1R1 antagonists or small interfering RNA–mediated silencing of IL-1R1 expression. Overexpression of mature miR-135b in NIH3T3 cells (pEGP-mmu-mir-135b) resulted in the suppression of endogenous levels of IL-1R1 expression. pEGP-mmu-miR-135b cells transiently transfected with luciferase reporter vector containing the 3′UTR of mouse IL-1R1 showed reduced luciferase activity. Finally, we demonstrate that miR-135b targets IL-1–stimulated activation of Caspase-1, the IL-1R1 downstream activator of IL-1β leading to suppressed synthesis of the active form of IL-1β protein. These results suggest that miR-135b expression during cigarette smoke–induced inflammation is regulated by IL-1R1 in a regulatory feedback mechanism to resolve inflammation.

The role of microRNAs in chronic respiratory disease: recent insights

“…An additional study in smokeexposed mice found that miR-135b abundance increased in the respiratory tract (Halappanavar et al, 2013). miR135b decreased the expression of interleukin 1 receptor (IL-1R1) through its 3′ UTR and was also a target of signaling through the IL-1 pathway, suggesting this miRNA as a critical regulator of IL-1-mediated neutrophilic inflammation (Halappanavar et al, 2013). Furthermore, miR-218-5p was found to be significantly downregulated in lung tissue of smoke-exposed mice and humans (Conickx et al, 2017).…”

“…Higher levels of smoke exposure corresponded to greater alterations in more miRNAs, most of which returned to baseline following smoking cessation, though some did not (Izzotti et al, 2011). An additional study in smokeexposed mice found that miR-135b abundance increased in the respiratory tract (Halappanavar et al, 2013). miR135b decreased the expression of interleukin 1 receptor (IL-1R1) through its 3′ UTR and was also a target of signaling through the IL-1 pathway, suggesting this miRNA as a critical regulator of IL-1-mediated neutrophilic inflammation (Halappanavar et al, 2013).…”

Unravelling the complexity of COPD by microRNAs: it's a small world after all

“…It is noteworthy that these miRNAs have human homologues and thus may be involved in the response to cigarette smoke exposure in humans as well. In a mouse model of 4 days' cigarette smoke exposure, miR-135b was shown by qRT-PCR to be increased in lung tissue samples [20]. The authors suggest that the upregulation of miR-135b may act as a counter-regulatory mechanism for cigarette smoke-induced inflammation, by regulating the IL-1 receptor (IL-1R1) expression.…”

MicroRNA-135b as therapeutic target in cancers

“…This immune-pulmonary cell microenvironment is the foundation of the pulmonary innate and/or adaptive immune systems [25] . Recently, a research group has reported a series of results showing the dominant up-regulation of miR-135b in lung tissues upon exposure to cigarette smoke and nano-particles in mice models [26][27][28] . The activated miR-135b is mediated through the IL-1a/IL-1R pathway, which consequently triggers either the acute or chronic pulmonary inflammation signaling cascade [26][27][28] .…”

“…In addition, using miR-135b inhibitors, several researchers have shown that silencing of miR-135b mitigates tumor burden, relieves lung metastatic nodules, and even rescues APC-knockout caused phenotypes [18,22] . Furthermore, miR-135b displays immuno-modulatory ability by cross-talking with pro-inflammatory cytokines and T cells in anaplastic large-cell lymphoma (ALCL) and in lung cancers [26,31] . Thus, miR-135 inhibition may further block the communication between tumor cells and its surrounding cancer niche.…”