Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A

Abstract

Neutrophils are the primary effector cells during inflammation, but can also control excessive inflammatory responses by secreting anti-inflammatory cytokines. However, the mechanisms modulating their plasticity remain unclear. We now show that systemic serum amyloid A-1 (SAA-1) controls the plasticity of neutrophil differentiation. SAA-1 not only induced anti-inflammatory IL-10-secreting neutrophils but also promoted invariant NKT (iNKT) cell interaction with these neutrophils, a process that limits their suppressive activity by reducing IL-10 and enhancing IL-12 production. Because SAA-1-producing melanomas promote differentiation of IL-10-secreting neutrophils, harnessing iNKT cells could be useful therapeutically by reducing the frequency of immunosuppressive neutrophils and restoring tumor specific immune responses.

Neutrophil transcriptional profile changes during transit from bone marrow to sites of inflammation

“…15,[42][43][44] The neutrophil literature contains numerous methodologies for neutrophil purification; ranging from density gradient centrifugation to immunomagnetic selection, cell sorting and culture models. 14,41,[45][46][47] In this study, obtaining high-quality mRNA from neutrophils for all three compartments was the greatest obstacle and required the most amount of refining. While the current optimal method for obtaining pure neutrophils is immunomagnetic negative selection, 15,43,48 this approach resulted in very low cell yields (loss of up to 90% of neutrophils-see the section on 'Materials and methods') and low mRNA quality.…”

Acute Phase Proteins: Structure and Function Relationship

“…SAA induces the differentiation of interleukin 10 (IL-10)-secreting neutrophils via signaling dependent on the G proteincoupled protein FPR2 (formyl peptide receptor 2), but also promotes the interaction of neutrophils with invariant natural killer T cells (iNKT cells), restoring T cell proliferation by abolishing IL-10 secretion. The final process is dependent on the antigen-presenting molecule CD1d and co-stimulatory molecule CD40 and results in less production of IL-10 and enhanced production of IL-12, thus limiting the suppressive activity of neutrophils (De Santo et al, 2010). SAA may affect inflammatory responses by activating its putative receptor on neutrophils (FPRL1), leading to increased production of IL-8 (He et al, 2003).…”

Contribution of cytokines to pathology and protection in virus infection

“…This regulatory neutrophil profile is turned into a pro--inflammatory one by CD1--dependent interaction between NKT cells and neutrophils [92], thus suggesting a mechanism also for the observations made in influenza infection.…”