Morphine compromises bronchial epithelial TLR2/IL17R signaling crosstalk, necessary for lung IL17 homeostasis

Sci Rep. 2015 Jun 15;5:11384. doi: 10.1038/srep11384.

Abstract

Opportunistic lung infection and inflammation is a hallmark of chronic recreational/clinical use of morphine. We show that early induction of IL17 from the bronchial epithelium, following pathogenic encounter is a protective response, which contributes to pathogenic clearance and currently attributed to TLR2 activation in immune cells. Concurrent activation of TLR2 and IL17R in bronchial epithelium results in the sequestration of MyD88 (TLR2 adapter) by Act1/CIKS (IL17R adapter), thereby turning off TLR2 signaling to restore homeostasis. Morphine inhibits the early IL17 release and interaction between Act1 and MyD88, leading to decreased pathogenic clearance and sustained inflammation. Hence, we propose that therapeutically targeting either TLR2 or IL17 in bronchial epithelia, in the context of morphine, can restore inflammatory homeostasis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Gene Expression Regulation
  • Homeostasis
  • Humans
  • Inflammation
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Lung / immunology*
  • Lung / microbiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphine / adverse effects*
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology
  • Pneumococcal Infections / etiology
  • Pneumococcal Infections / immunology*
  • Pneumococcal Infections / microbiology
  • Pneumococcal Infections / pathology
  • Receptor Cross-Talk / drug effects
  • Receptor Cross-Talk / immunology
  • Receptors, Interleukin-17 / genetics
  • Receptors, Interleukin-17 / immunology*
  • Receptors, Opioid, mu / deficiency
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / immunology
  • Signal Transduction
  • Streptococcus pneumoniae / immunology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / immunology*
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Interleukin-17
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-17
  • Receptors, Opioid, mu
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Traf3ip2 protein, mouse
  • Morphine