cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner.
Loss of inhibitor of apoptosis proteins (IAPs), particularly cIAP1, can promote production of tumor necrosis factor (TNF) and sensitize cancer cell lines to TNF-induced necroptosis by promoting formation of a death-inducing signaling complex containing receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3. To define the role of IAPs in myelopoiesis, we generated a mouse with cIAP1, cIAP2, and XIAP deleted in the myeloid lineage. Loss of cIAPs and XIAP in the myeloid lineage caused overproduction of many proinflammatory cytokines, resulting in granulocytosis and severe sterile inflammation. In vitro differentiation of macrophages from bone marrow in the absence of cIAPs and XIAP led to detectable levels of TNF and resulted in reduced numbers of mature macrophages. The cytokine production and consequent cell death caused by IAP depletion was attenuated by loss or inhibition of TNF or TNF receptor 1. The loss of RIPK1 or RIPK3, but not the RIPK3 substrate mixed lineage kinase domain-like protein, attenuated TNF secretion and thereby prevented apoptotic cell death and not necrosis. Our results demonstrate that cIAPs and XIAP together restrain RIPK1- and RIPK3-dependent cytokine production in myeloid cells to critically regulate myeloid homeostasis.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
W Wei-Lynn
WW
Wong
James E
JE
Vince
Najoua
N
Lalaoui
Kate E
KE
Lawlor
Diep
D
Chau
Aleksandra
A
Bankovacki
Holly
H
Anderton
Donald
D
Metcalf
Lorraine
L
O'Reilly
Philipp J
PJ
Jost
James M
JM
Murphy
Warren S
WS
Alexander
Andreas
A
Strasser
David L
DL
Vaux
John
J
Silke
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D017353:Gene Deletion; D006098:Granulocytes / Q000502:physiology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038042:Myelopoiesis / Q000235:genetics*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology*; D013163:Splenomegaly / Q000235:genetics / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000502:physiology*
D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse