Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo

Abstract

Neutrophil extracellular traps (NETs) are released, as neutrophils die in vitro, in a process requiring hours, leaving a temporal gap for invasive microbes to exploit. Functional neutrophils undergoing NETosis have not been documented. During Gram-positive skin infections, we directly visualized live PMN in vivo rapidly releasing NETs, which prevented bacterial dissemination. NETosis occurred during crawling thereby casting large areas of NETs. NET-releasing PMN developed diffuse decondensed nuclei ultimately becoming devoid of DNA. Cells with abnormal nuclei displayed unusual crawling behavior highlighted by erratic pseudopods and hyperpolarization consistent with the nucleus being a fulcrum for crawling. A combined requirement of Tlr2 and complement mediated opsonization tightly regulated NET release. Additionally live human PMN developed decondensed nuclei and formed NETS in vivo and intact anuclear neutrophils were abundant in Gram-positive human abscesses. Therefore early in infection, non-cell death NETosis occurs in vivo during Gram-positive infection in mice and humans.

Changing world of neutrophils

“…In all these experiments, destruction of the DNA scaffold of NETs by iv. administered DNase resulted in an increase of bacteremia or number of virus-infected cells [49,71,124]. Thus, NET formation clearly prevents dissemination of microorganisms.…”

“…Instead, viable but anuclear granulocytes continued to crawl in a chemical gradient and to phagocytose [124]. In a septic model, rapid platelet-dependent NET formation was observed in liver sinusoids that increased trapping of bacteria by four-fold [71].…”

Antimicrobial Histones and DNA Traps in Invertebrate Immunity

“…More recently, those extracellular traps (ETs) 5 have been observed to form massively in infected tissues by intravital microscopy, demonstrating further their role in host defense (10). ETs can be released in response to bacteria, fungi, parasites, and viruses (9,11,12), to microbe-associated molecular patterns such as lipopolysaccharide (LPS), and to host inflammatory signals associated with tissue damage such as interleukin-8 (9) and tumor necrosis factor (13).…”

“…However, some bacteria such as Streptococcus pneumoniae, Mycobacterium tuberculosis, and group A Streptococci are found entrapped into ETs without being killed (17,18). ETs can then play two important roles in the control of infections, first by entrapping microbes and preventing their dissemination, and second by concentrating antimicrobials and potentially killing microbes (10,16,19).…”

La pêche miraculeuse des filets du neutrophile

“…L'intervention des NET est essentielle pour lutter contre les micro-organismes trop grands pour être phagocytés, comme les hyphes fongiques ou les helminthes. Ainsi, l'absence de nétose chez les patients atteints de granulomatose septique chronique (mutaconservaient leur capacité de migration et de phagocytose après la nétose [9]. Ce mécanisme rapide permettrait d'expliquer le rôle de la nétose dans certains phénomènes aigus.…”