IRG1/ACOD1 promotes neutrophil reverse migration and alleviates local inflammation.

Polymorphonuclear neutrophil (PMN) infiltration at inflammatory site plays a critical role in inflammation. PMN reverse migration (rM) describes the phenomenon that PMNs migrate away from inflammatory site back into the vasculature, and its role within inflammatory scenarios remains to be fully determined. This study aimed to investigate the mechanism underlying PMN rM and its role in inflammation. First, we demonstrated PMN rM in a mouse model of lipopolysaccharide-induced acute lung inflammation. By single-cell RNA sequencing, we demonstrated that reverse migrated (rM-ed) PMNs in blood expressed a high level of immune-responsive gene 1 (Irg1), the encoding gene of cis-aconitate decarboxylase (ACOD1). Using a mouse air pouch model, which enabled us to directly track rM-ed PMNs in vivo, we detected higher expression of ACOD1 in the rM-ed PMNs in circulation. Furthermore, mice with Irg1 knockout exhibited decreased PMN rM and higher levels of inflammatory cytokine in inflammatory site. Mechanistically, we found that itaconate, the product of ACOD1 catalyzation, decreased PMN ICAM-1 expression at the inflammation site. Furthermore, inflammatory site showed a high level of shed Cd11a, the ligand of ICAM-1. Neutralization of either ICAM-1 or Cd11a led to increased PMN rM. These findings suggest that the binding of ICAM-1 and shed Cd11a serves as a retaining force to hold PMNs in the site of inflammation, and ACOD1-decreased PMN surface expression of ICAM-1 weakens the retaining force, promoting PMNs to leave the inflammatory site. These results indicate a regulatory role of IRG1 in PMN rM and subsequent contributions to inflammation resolution.

Biomineralized Nanoscavenger Abrogates Proinflammatory Macrophage Polarization and Induces Neutrophil Clearance through Reverse Migration during Gouty Arthritis.

The deposition of monosodium urate (MSU) crystals induces the overexpression of reactive oxygen species (ROS) and proinflammatory cytokines in residential macrophages, further promoting the infiltration of inflammatory leukocytes in the joints of gouty arthritis. Herein, a peroxidase-mimicking nanoscavenger was developed by forming manganese dioxide over albumin nanoparticles loaded with an anti-inflammatory drug, indomethacin (BIM), to block the secretion of ROS and COX2-induced proinflammatory cytokines in the MSU-induced gouty arthritis model. In the MSU-induced arthritis mouse model, the BIM nanoparticles alleviated joint swelling, which is attributed to the abrogation of ROS and inflammatory cytokine secretions from proinflammatory macrophages that induces neutrophil infiltration and fluid building up in the inflammation site. Further, the BIM nanoparticle treatment reduced the influx of macrophages and neutrophils in the injured region by blocking migration and inducing reverse migration in the zebrafish larva tail amputation model as well as in MSU-induced peritonitis and air pouch mouse models. Overall, the current strategy of employing biomineralized nanoscavengers for arthritis demonstrates clinical significance in dual blocking of peroxides and COX2 to prevent influx of inflammatory cells into the sites of inflammation.

Neutrophil reverse migration.

The behavior of neutrophils is very important for the resolution of inflammation and tissue repair. People have used advanced imaging techniques to observe the phenomenon of neutrophils leaving the injured or inflammatory site and migrating back into blood vessels in transgenic zebrafish and mice, which is called neutrophil reverse migration. Numerous studies have shown that neutrophil reverse migration is a double-edged sword. On the one hand, neutrophil reverse migration can promote the resolution of local inflammation by accelerating the clearance of neutrophils from local wounds. On the other hand, neutrophils re-enter the circulatory system may lead to the spread of systemic inflammation. Therefore, accurate regulation of neutrophil reverse migration is of great significance for the treatment of various neutrophil- mediated diseases. However, the mechanism of neutrophil reverse migration and its relationship with inflammation resolution is unknown. In this review, we reviewed the relevant knowledge of neutrophil reverse migration to elucidate the potential mechanisms and factors influencing reverse migration and its impact on inflammation in different disease processes.

Deletion of cftr Leads to an Excessive Neutrophilic Response and Defective Tissue Repair in a Zebrafish Model of Sterile Inflammation.

Inflammation-related progressive lung destruction is the leading causes of premature death in cystic fibrosis (CF), a genetic disorder caused by a defective cystic fibrosis transmembrane conductance regulator (CFTR). However, therapeutic targeting of inflammation has been hampered by a lack of understanding of the links between a dysfunctional CFTR and the deleterious innate immune response in CF. Herein, we used a CFTR-depleted zebrafish larva, as an innovative in vivo vertebrate model, to understand how CFTR dysfunction leads to abnormal inflammatory status in CF. We show that impaired CFTR-mediated inflammation correlates with an exuberant neutrophilic response after injury: CF zebrafish exhibit enhanced and sustained accumulation of neutrophils at wounds. Excessive epithelial oxidative responses drive enhanced neutrophil recruitment towards wounds. Persistence of neutrophils at inflamed sites is associated with impaired reverse migration of neutrophils and reduction in neutrophil apoptosis. As a consequence, the increased number of neutrophils at wound sites causes tissue damage and abnormal tissue repair. Importantly, the molecule Tanshinone IIA successfully accelerates inflammation resolution and improves tissue repair in CF animal. Our findings bring important new understanding of the mechanisms underlying the inflammatory pathology in CF, which could be addressed therapeutically to prevent inflammatory lung damage in CF patients with potential improvements in disease outcomes.