Differentiated macrophages acquire a pro-inflammatory and cell death–resistant phenotype due to increasing xiap and p38-mediated inhibition of ripk1

TY - JOUR

T1 - Differentiated macrophages acquire a pro-inflammatory and cell death–resistant phenotype due to increasing xiap and p38-mediated inhibition of ripk1

AU - Rijal, Dikchha

AU - Ariana, Ardeshir

AU - Wight, Andrew

AU - Kim, Kwangsin

AU - Alturki, Norah A.

AU - Aamir, Zoya

AU - Ametepe, Emmanuelle S.

AU - Korneluk, Robert G.

AU - Tiedje, Christopher

AU - Menon, Manoj B.

AU - Gaestel, Matthias

AU - McComb, Scott

AU - Sad, Subash

PY - 2018/7/27

Y1 - 2018/7/27

N2 - Monocytes differentiate into macrophages, which deactivate invading pathogens. Macrophages can be resistant to cell death mechanisms in some situations, and the mechanisms involved are not clear. Here, using mouse immune cells, we investigated whether the differentiation of macrophages affects their susceptibility to cell death by the ripoptosome/necrosome pathways. We show that treatment of macrophages with a mimetic of second mitochondrial activator of caspases (SMAC) resulted in ripoptosome-driven cell death that specifically depended on tumor necrosis factor (TNF) expression and the receptor-interacting serine/threonine protein kinase 1 (RipK1)–RipK3–caspase-8 interaction in activated and cycling macrophages. Differentiation of macrophages increased the expression of pro-inflammatory cytokines but reduced RipK1-dependent cell death and the RipK3– caspase-8 interaction. The expression of the anti-apoptotic mediators, X-linked inhibitor of apoptosis protein (XIAP) and caspase-like apoptosis regulatory protein (cFLIPL), also increased in differentiated macrophages, which inhibited caspase activation. The resistance to cell death was abrogated in XIAP-deficient macrophages. However, even in the presence of increased XIAP expression, inhibition of the mitogen-activated protein kinase (MAPK) p38 and MAPK-activated protein kinase 2 (MK2) made differentiated macrophages susceptible to cell death. These results suggest that the p38/ MK2 pathway overrides apoptosis inhibition by XIAP and that acquisition of resistance to cell death by increased expression of XIAP and cFLIPL may allow inflammatory macrophages to participate in pathogen control for a longer duration.

AB - Monocytes differentiate into macrophages, which deactivate invading pathogens. Macrophages can be resistant to cell death mechanisms in some situations, and the mechanisms involved are not clear. Here, using mouse immune cells, we investigated whether the differentiation of macrophages affects their susceptibility to cell death by the ripoptosome/necrosome pathways. We show that treatment of macrophages with a mimetic of second mitochondrial activator of caspases (SMAC) resulted in ripoptosome-driven cell death that specifically depended on tumor necrosis factor (TNF) expression and the receptor-interacting serine/threonine protein kinase 1 (RipK1)–RipK3–caspase-8 interaction in activated and cycling macrophages. Differentiation of macrophages increased the expression of pro-inflammatory cytokines but reduced RipK1-dependent cell death and the RipK3– caspase-8 interaction. The expression of the anti-apoptotic mediators, X-linked inhibitor of apoptosis protein (XIAP) and caspase-like apoptosis regulatory protein (cFLIPL), also increased in differentiated macrophages, which inhibited caspase activation. The resistance to cell death was abrogated in XIAP-deficient macrophages. However, even in the presence of increased XIAP expression, inhibition of the mitogen-activated protein kinase (MAPK) p38 and MAPK-activated protein kinase 2 (MK2) made differentiated macrophages susceptible to cell death. These results suggest that the p38/ MK2 pathway overrides apoptosis inhibition by XIAP and that acquisition of resistance to cell death by increased expression of XIAP and cFLIPL may allow inflammatory macrophages to participate in pathogen control for a longer duration.

U2 - 10.1074/jbc.ra118.003614

DO - 10.1074/jbc.ra118.003614

M3 - Journal article

C2 - 29899110

AN - SCOPUS:85050778262

SN - 0021-9258

VL - 293

SP - 11913

EP - 11927

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 30

ER -