Granzyme K synergistically potentiates LPS-induced cytokine responses in human monocytes.
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.
Department of Pathology and Laboratory of Translational Immunology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.
Annette C
AC
Wensink
Vera
V
Kemp
Job
J
Fermie
M Isabel
MI
García Laorden
Tom
T
van der Poll
C Erik
CE
Hack
Niels
N
Bovenschen
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000378:metabolism; D016905:Gram-Negative Bacterial Infections / Q000097:blood; D053804:Granzymes / Q000097:blood / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008823:Micelles; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D018805:Sepsis / Q000097:blood / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008823:Micelles; D014409:Tumor Necrosis Factor-alpha; D053804:Granzymes