Negative regulation of Toll-like receptor 4 signaling by IL-10–dependent microRNA-146b

Abstract

Toll-like receptors (TLRs) play key roles in detecting pathogens and initiating inflammatory responses that, subsequently, prime specific adaptive responses. Several mechanisms control TLR activity to avoid excessive inflammation and consequent immunopathology, including the anti-inflammatory cytokine IL-10. Recently, several TLR-responsive microRNAs (miRs) have also been proposed as potential regulators of this signaling pathway, but their functional role during the inflammatory response still is incompletely understood. In this study, we report that, after LPS engagement, monocytes up-regulate miR-146b via an IL-10–mediated STAT3-dependent loop. We show evidence that miR-146b modulates the TLR4 signaling pathway by direct targeting of multiple elements, including the LPS receptor TLR4 and the key adaptor/signaling proteins myeloid differentiation primary response (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK-1), and TNF receptor-associated factor 6 (TRAF6). Furthermore, we demonstrate that the enforced expression of miR-146b in human monocytes led to a significant reduction in the LPS-dependent production of several proinflammatory cytokines and chemokines, including IL-6, TNF-α, IL-8, CCL3, CCL2, CCL7, and CXCL10. Our results thus identify miR-146b as an IL-10–responsive miR with an anti-inflammatory activity based on multiple targeting of components of the TLR4 pathway in monocytes and candidate miR-146b as a molecular effector of the IL-10 anti-inflammatory activity.

In vitro screening of LPS-induced miRNAs in leukocytes derived from cord blood and their possible roles in regulating TLR signals

“…The upregulation of miR-146 after LPS stimulation was also observed in monocytes derived from adult peripheral veins and from newborn CB (11). After LPS engagement, monocytes upregulate miR-146b which modulates the TLR4 signaling pathway by direct targeting of multiple elements, including TLR4, MyD88, IRAK-1, and TRAF6, via an IL-10-mediated STAT3-dependent loop (26). In addition, activation of the MAP kinase/EGR pathway by proinflammatory cytokines regulates the transcription of the miR-146, which can in turn repress the NF-κB, AP-1, and MAPK/EGR pathways.…”

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

“…Interestingly, miR146b-5p (P ϭ 00873), an LPS-responsive miRNA, showed statistically nonsignificant elevation at 180 dpi. Recent in vitro studies showed miR-146b-5p to be significantly upregulated following LPS treatment of THP monocytes; however, they showed delayed kinetics (39). This raised the question of whether translocated luminal bacteria and their products in the lamina propria (47) are triggering miR-146b-5p upregulation.…”

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Alternatively, methods for manipulating anti-inflammatory cytokines such as IL-10 may yield some promise for treating drug-induced inflammation. IL-10 is a powerful suppressor of TLR-induced cytokine production (Curtale et al, 2013). In addition, IL-10 treatment has proven successful at treating animal models of neuropathic pain (Dengler et al, 2014;Kwilasz et al, 2015).…”