Neutrophil Extracellular Traps Induced by IL8 Promote Diffuse Large B-cell Lymphoma Progression via the TLR9 Signaling

Abstract

Purpose: More than 30% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment failure after firstline therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism.Experimental Design: NETs in DLBCL tumor samples and plasma were detected by immunofluorescence and ELISA, respectively. The correlation between NETs and clinical features were analyzed. The effects of NETs on cellular proliferation and migration and mechanisms were explored, and the mechanism of NET formation was also studied by a series of in vitro and in vivo assays.Results: Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in patients with DLBCL. Furthermore, we identified NETs increased cell proliferation and migration in vitro and tumor growth and lymph node dissemination in vivo. Mechanistically, DLBCL-derived IL8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38, and ERK signaling. Newly formed NETs directly upregulated the Toll-like receptor 9 (TLR9) pathways in DLBCL and subsequently activated NFkB, STAT3, and p38 pathways to promote tumor progression. More importantly, disruption of NETs, blocking IL8-CXCR2 axis or inhibiting TLR9 could retard tumor progression in preclinical models.Conclusions: Our data reveal a tumor-NETs aggressive interaction in DLBCL and indicate that NETs is a useful prognostic biomarker and targeting this novel cross-talk represents a new therapeutic opportunity in this challenging disease.

Exosomal KRAS mutation promotes the formation of tumor-associated neutrophil extracellular traps and causes deterioration of colorectal cancer by inducing IL-8 expression

“…As previous study reported, IL-8 may bind to IL-8-R1/2 in the neutrophil membrane to shuttle neutrophils to tumors [28,29]. Meanwhile, IL-8 could promote the formation of NET by activating Src, ERK and p38 signaling [30]. Nevertheless, the molecular mechanism of IL-8 function on regulating formation of NETs is lack of details, which should be paid more attention in the following experimentation.…”

The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury

“…However, growing evidence suggests that aberrant activation of these TLRs with self DNA and/or RNA occur when free nucleic material is present in the tissue, such as in autoimmune diseases, viral infections, and following traumatic injuries. 17,[25][26][27][28][29][30][31] Small molecule inhibitors of TLR7/8/9, such as hydroxychloroquine (HCQ, Plaquenil®), were developed initially as anti-malarial agents, but have shown to be efficacious for treating lupus, an autoimmune disease characterized by excess and impaired degradation of NETs. 13,24,[32][33][34] HCQ has also been shown to be an effective antiviral agent against RNA viruses including dengue virus and retroviruses 35 by de-acidifying endosomes required for endosome-mediated viral entry during TLR7/8/9 activation.…”

Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression

“…Indeed, increased secretion of IL-8 secretions has been reported in various human malignancies, and IL-8 is involved in more aggressive phenotypes [38][39][40][41]. Functional modulation of tumor-associated neutrophils by IL-8 has also been described as a poor prognostic factor for malignancies [39,42]. As the tumor promoting effect of Dnm3os via cancer-associated fibroblasts was also demonstrated in esophageal cancer [43], dynamic modulation of the tumor microenvironment might also be achieved by the Dnm3os/miR-214 axis.…”