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

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.

N‐myc and STAT interactor correlates with severity and prognosis in acute‐on‐chronic liver failure of hepatitis B virus

“…report that upregulation of NMI correlated with inflammatory signature in the patients with congenital erythrocyte aplasia . Serum NMI is also found to be correlated to the severity of inflammation and mortality of patients with sepsis . HBV‐ACLF syndrome has some similarities to sepsis, suggesting that NMI may also involve in the progression of HBV‐ACLF.…”

“…NMI is also involved in antiviral response against viral infections . Recently, it is demonstrated that NMI correlates with the severity of inflammation in sepsis patients . The severity of ACLF is also correlated with inflammation, which is contributing to prognosis of ACLF .…”

“…NMI is typically localized to the cytoplasm and ubiquitously expressed, especially in the liver . NMI plays regulatory roles in immune cells, including T cells, natural killer cells, and macrophages . NMI enhances immune function via STAT‐mediated transcription in response to inflammatory stimulation .…”

“…NMI enhances immune function via STAT‐mediated transcription in response to inflammatory stimulation . It is reported that macrophages‐derived NMI promotes inflammation in different inflammation models . NMI is elevated rapidly in acetaminophen‐induced liver injury .…”

“…It is reported that macrophages‐derived NMI promotes inflammation in different inflammation models . NMI is elevated rapidly in acetaminophen‐induced liver injury . NMI is also involved in antiviral response against viral infections .…”