Neutrophil extracellular traps exert both pro- and anti-inflammatory actions in rheumatoid arthritis that are modulated by C1q and LL-37.

Dual activity of NET. Activated PMN enter NETosis in response to some stimuli. In RA, PMN are significantly more sensitive to NETosis triggering. These NET directly activate (pink arrows) steady state PMN (left) and macrophages (MΦ, right), leading to strong IL-8, TNF and IL-6 secretion (three important cytokines in RA) but low IL-10 induction, i.e. a pro-inflammatory profile. In addition, RA NET are significantly more stimulatory than normal NET. Although NET are recognized by ACPA, the resulting immune complexes do not clearly enhance PMN and MΦ response to NET. Likewise, endosomal TLR are probably not involved in NET sensing. Regarding MΦ, NET-induced activation is specifically increased in the presence of DNA-binding molecules like C1q and LL-37 (blue arrows). C1q in combination with LL-37 carry NET to PMN and MΦ which express surface C1q and LL-37 receptors (C1qR, LL-37-R). Because MΦ express much more C1qR than PMN, MΦ (and not PMN) activation by NET is enhanced by C1q or C1q/LL-37. On the contrary, NET induce an anti-inflammatory profile in strongly-activated MΦ but not PMN (green arrows). Indeed, NET specifically (partly) inhibit secretion of the pro-inflammatory cytokine IL-6 by MΦ in response to LPS, especially in the presence of both C1q and LL-37, and inversely enhance IL-10 secretion by those MΦ.Image 1