The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls.
Systemic infection with Streptococcus pneumoniae is associated with a vigorous pro-inflammatory response to structurally complex cell wall fragments (PnCW) that are shed during cell growth and antibiotic-induced autolysis. Consistent with previous studies, inflammatory cytokine production induced by PnCW was dependent on TLR2 but independent of NOD2, a cytoplasmic NLR protein. However, in parallel with the pro-inflammatory response, we found that PnCW also induced prodigious secretion of anti-inflammatory IL-10 from macrophages. This response was dependent on TLR2, but also involved NOD2 as absence of NOD2-reduced IL-10 secretion in response to cell wall and translated into diminished downstream effects on IL-10-regulated target gene expression. PnCW-mediated production of IL-10 via TLR2 required RIPK2 a kinase required for NOD2 function, and MyD88 but differed from that known for zymosan in that ERK pathway activation was not detected. As mutations in NOD2 are linked to aberrant immune responses, the temporal and quantitative effects of activation of the TLR2-NOD2-RIPK2 pathway on IL-10 secretion may affect the balance between pro- and anti-inflammatory responses to Gram-positive bacteria.
Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Lilian O
LO
Moreira
Karim C
KC
El Kasmi
Amber M
AM
Smith
David
D
Finkelstein
Sophie
S
Fillon
Yun-Gi
YG
Kim
Gabriel
G
Núñez
Elaine
E
Tuomanen
Peter J
PJ
Murray
D000818:Animals; D002473:Cell Wall / Q000276:immunology*; D002478:Cells, Cultured; D007249:Inflammation / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000276:immunology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016753:Interleukin-10; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse