NMI and IFP35 serve as proinflammatory DAMPs during cellular infection and injury

Zhikai Xiahou,Juan Shen,Yong Tian,Henan Li,Xiaoxiao Zhu,Huanhuan Liang,Feng Xu,Yingfang Liu,Rong Hu,Xiangli Wang,Deyin Guo

doi:10.1038/s41467-017-00930-9

Abstract

Damage-associated molecular patterns (DAMP) trigger innate immune response and exacerbate inflammation to combat infection and cellular damage. Identifying DAMPs and revealing their functions are thus of crucial importance. Here we report that two molecules, N-myc and STAT interactor (NMI) and interferon-induced protein 35 (IFP35) act as DAMPs and are released by activated macrophages during lipopolysaccharide-induced septic shock or acetaminophen-induced liver injury. We show that extracellular NMI and IFP35 activate macrophages to release proinflammatory cytokines by activating nuclear factor-κB through the Toll-like receptor 4 pathway. In addition, the serum levels of NMI are increased in patients who succumbed to severe inflammation. NMI deficiency reduces inflammatory responses and mortality in mouse models of sepsis and liver injury. We therefore propose that extracellular NMI and IFP35 exacerbate inflammation as DAMPs, making them potential therapeutic targets for clinical intervention.

Highlights

Damage-associated molecular patterns (DAMP) trigger innate immune response and exacerbate inflammation to combat infection and cellular damage
Upon DAMP binding, pattern recognition receptors (PRR) trigger the activation of nuclear factor-κB (NF-κB), resulting in the acute expression and release of proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin 1β and interleukin 6 (IL-6)
During the investigation of various interferon (IFN)-stimulated genes of unknown functions, we identified two DAMPs, N-myc and signal transducer and activator of transcription (STAT) interactor (NMI) and IFN-induced protein 35 (IFP35), that belong to the IFP35 family[18,19,20]

Summary

Introduction

Damage-associated molecular patterns (DAMP) trigger innate immune response and exacerbate inflammation to combat infection and cellular damage. Upon DAMP binding, PRRs trigger the activation of nuclear factor-κB (NF-κB), resulting in the acute expression and release of proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin 1β and interleukin 6 (IL-6) These cytokines recruit granulocytes to the infected or injured tissues, stimulate lymphocyte differentiation, and promote inflammation[1,2,3]. Existing reports suggest that intracellular NMI and IFP35 are negative regulators of innate immune signaling pathways, targeting retinoic acid-inducible gene I, nuclear factor IFN regulatory factor 7 and NF-κB29–31 Different from these intracellular functions, here we investigate the extracellular functions of NMI and IFP35. Our results provide evidence that both proteins are actively released by macrophage to extracellular space during cell injury and pathogen invasion These extracellular NMI and IFP35 activate the NF-κB signaling pathway of adjacent macrophages through TLR4 and promote their release of TNF, serving as proinflammatory DAMPs

Methods

Results

Conclusion