Neutrophils come of age in chronic inflammation

Abstract

Neutrophils have long been known to participate in acute inflammation, but a role in chronic inflammatory and autoimmune diseases is now emerging. These cells are key players in the recognition and elimination of pathogens, but they also sense self components, including nucleic acids and products of sterile tissue damage. While this normally contributes to tissue repair, it can also lead to the release of highly immunogenic products that can trigger and/or amplify autoimmune pathogenic loops. Understanding the mechanisms that underlie neutrophil activation, migration, survival and their various forms of death in health and disease might provide us with new approaches to treat chronic inflammatory conditions.

Figure 1

(A) Under resting conditions (upper left), neutrophils constitutively express FcgR and endosomal TLRs. Proteases and antimicrobial peptides are stored in cytoplasmic granules. (B) Upon priming with cytokines such as TNFα, granular proteins are translocated to the plasma membrane. IFNα induces TR7 expression and promotes the translocation of anti-microbial peptides (i.e. LL37) to the plasma membrane. (C) Upper left: activation with bacterial can lead to the release of microparticles containing chromatin/DNA. This can eventually lead to total enucleation. Mitochondria from damaged cells can be internalized and activate endosomal TLR9; LPS-activation in turn leads to the extrusion of mitochondrial-derived DAMPs that can activate other cells. Upper right: activation with ANCA-MPO/PR3 might leads to NETosis and/or the release of microparticles displaying surface ANCA-related antigens. In addition, this type of activation can induce secretion of B cell-activating factors (BLyS/BAFF) and/or cytokines such as IL17. Bottom: activation with SLE-derived anti-RNP antibodies or anti-LL37 antibodies leads to extrusion of immunogenic DNA in the form of NETs.