Irf5 deficiency in myeloid cells prevents necrotizing enterocolitis by inhibiting M1 macrophage polarization

Jia Wei,Yidong Wang,Qiang Shu,Jin Yang,Chengjie Lu,Jianfang Wang,Yulei Lu,Zhejun Cai,Liangliang Jia,Yi Lu,Wei Ru,Daxing Tang

doi:10.1038/s41385-019-0169-x

Abstract

Necrotizing enterocolitis (NEC) is a life-threatening inflammatory disease in newborns, but the mechanisms remain unclear. Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage function and is essential for proinflammatory M1 macrophage polarization. Our previous data indicated that M1 macrophages promote NEC injury. Here, we investigated whether IRF5 is involved in the pathogenesis of NEC. First, we found that IRF5 was upregulated in infiltrated macrophages in human neonates with NEC compared to controls. We further confirmed IRF5 upregulation in macrophages in experimental murine NEC and that the infiltrated macrophages were predominantly polarized into the M1 but not the M2 phenotype. Myeloid-specific deficiency of Irf5, which was associated with reduced M1 macrophage polarization and systematic inflammation, dramatically prevented experimental NEC. Moreover, we found that the ablation of Irf5 in myeloid cells markedly suppressed intestinal epithelial cell apoptosis and further prevented intestinal barrier dysfunction in experimental NEC. Bioinformatic and chromatin immunoprecipitation analysis further showed that IRF5 binds to the promoters of the M1 macrophage-associated genes Ccl4, Ccl5, Tnf, and Il12b. Overall, our study provides evidence that IRF5 participates in the pathogenesis of NEC, while the deletion of Irf5 in myeloid cells prevents NEC via inhibiting M1 macrophage polarization.

Highlights

Necrotizing enterocolitis (NEC) is a severe inflammatory disease that affects the gastrointestinal tract of premature infants and is the most common cause of gastrointestinal mortality in newborns.[1]
Interferon regulatory factor 5 (IRF5) is upregulated in macrophages in human neonates with NEC We first explored whether IRF5 is involved in NEC
Immunofluorescence analysis further showed a marked increase in the number of CD68-positive cells coexpressing IRF5, indicating that IRF5 was upregulated in infiltrated macrophages in neonates with NEC (Fig. 1b)

Summary

Introduction

Necrotizing enterocolitis (NEC) is a severe inflammatory disease that affects the gastrointestinal tract of premature infants and is the most common cause of gastrointestinal mortality in newborns.[1]. The average mortality from NEC is 20–30% and as high as 50% in infants who require surgical intervention.[3] Approximately half of NEC survivors suffer from early postoperative complications, such as wound infection, breakdown or dehiscence, and long-term complications including intestinal stricture and short-gut syndrome.[4] Despite several decades of studies on the pathogenesis of NEC, the detailed mechanisms remain incompletely understood. Microbial immaturity, intestinal barriers and the response to inflammation by the premature intestine are considered to be involved in the pathogenesis of NEC.[5] One of the critical pathological features of NEC is the accumulation of rich inflammatory cells that infiltrate the intestinal mucosa.[6,7] Studies have indicated that macrophages play an essential role in the development of NEC.[7] The premature innate immune system is associated with a hyperinflammatory intestinal macrophage phenotype that causes increased NEC injury.[8] macrophages promote nuclear factor (NF)-κB-mediated inflammatory signaling in NEC through toll-like receptors (TLRs) activation.[6,9]

Methods

Results

Conclusion