Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes

AC Wensink, V Kemp, J Fermie… - Proceedings of the …, 2014 - National Acad Sciences
AC Wensink, V Kemp, J Fermie, MI García Laorden, T van der Poll, CE Hack, N Bovenschen
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
Granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in
virus-infected cells and tumor cells. Evidence is emerging that granzymes also play a role in
controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune
diseases and infections, including sepsis. However, the function of extracellular granzymes
in inflammation largely remains unknown. Here, we show that granzyme K (GrK) binds to
Gram-negative bacteria and their cell-wall component lipopolysaccharide (LPS). GrK …
Granzymes are serine proteases released by cytotoxic lymphocytes to induce apoptosis in virus-infected cells and tumor cells. Evidence is emerging that granzymes also play a role in controlling inflammation. Granzyme serum levels are elevated in patients with autoimmune diseases and infections, including sepsis. However, the function of extracellular granzymes in inflammation largely remains unknown. Here, we show that granzyme K (GrK) binds to Gram-negative bacteria and their cell-wall component lipopolysaccharide (LPS). GrK synergistically enhances LPS-induced cytokine release in vitro from primary human monocytes and in vivo in a mouse model of LPS challenge. Intriguingly, these extracellular effects are independent of GrK catalytic activity. GrK disaggregates LPS from micelles and augments LPS–CD14 complex formation, thereby likely boosting monocyte activation by LPS. We conclude that extracellular GrK is an unexpected direct modulator of LPS–TLR4 signaling during the antimicrobial innate immune response.
National Acad Sciences