Journal
BLOOD
Volume 122, Issue 20, Pages 3473-3481Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-05-502229
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Funding
- Kidney Research UK [TF9.2009]
- MRC Research Grant [G1002165]
- Medical Research Council Centre for Transplantation, Guy's Hospital, King's College
- Department of Health, National Institute for Health Research comprehensive Biomedical Research Centre
- German Research Foundation [GRK1727 TP8, SFB/TR22 A21]
- Imperial College Healthcare NHS Trust Biomedical Research Centre
- MRC [G0600892, G1002165] Funding Source: UKRI
- Medical Research Council [G1002165, MR/J006742/1, G0600892] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10142] Funding Source: researchfish
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Interleukin-1 beta (IL-1 beta) is a proinflammatory cytokine and a therapeutic target in several chronic autoimmune states. Monocytes and macrophages are the major sources of IL-1 beta. IL-1 beta production by these cells requires Toll-like receptor (TLR) and adenosine triphosphate (ATP)-mediated P2X purinoceptor 7 (P2X7) signals, which together activate the inflammasome. However, how TLR signals and ATP availability are regulated during monocyte activation is unclear and the involvement of another danger signal system has been proposed. Here, we demonstrate that both lipopolysaccharide (LPS) and the anaphylatoxin C3a are needed for IL-1 beta production in human macrophages and dendritic cells, while in monocytes, C3a enhanced the secretion of LPS-induced IL-1 beta. C3a and LPS-stimulated monocytes increased T helper 17 (Th17) cell induction in vitro, and human rejecting, but not nonrejecting, kidney transplant biopsies were characterized by local generation of C3a and monocyte and Th17 cell infiltration. Mechanistically, C3a drives IL-1 beta production in monocytes by controlling the release of intracellular ATP into the extracellular space via regulation of as-yet unidentified ATP-releasing channels in an extracellular signal-regulated kinase 1/2-dependent fashion. These data define a novel function for complement in inflammasome activation in monocytes and suggest that C3aR-mediated signaling is a vital component of the IL-1 beta-Th17 axis.
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