Abstract
Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID.
Highlights
Neutrophils constitute the most abundant leukocytes in human peripheral blood and represent the first line defense against invading pathogens such as bacteria, fungi and certain viruses [1,2]
These data suggest that Fas ligand (FASL)-induced apoptosis may switch to RIPK1- and RIPK3-dependent cell death when caspases are blocked and that, interestingly, BH3 interacting domain death agonist (BID) seems to contribute to such a switch
Their lifespan has to be tightly controlled, especially once they enter an activated state, and neutrophil cell death is achieved amongst others by engagement of the death receptor FAS, which is constitutively expressed on neutrophils [1,2,11]
Summary
Neutrophils constitute the most abundant leukocytes in human peripheral blood and represent the first line defense against invading pathogens such as bacteria, fungi and certain viruses [1,2]. In the absence of infections, neutrophils are rapidly turned over by spontaneous apoptosis with an estimated lifespan of no more than a few days [3,4] Bacterial components such as LPS and pro-inflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) prolong survival of neutrophils, which is crucial for an efficient antimicrobial response, by induction of anti-apoptotic genes, including MCL-1, BFL-1/BCL-2-A1 or X-linked inhibitor of apoptosis (XIAP) [5,6,7,8]. Soluble FASL induces cytokine production and survival whereas only the membrane-bound form can elicit cell death [20]. Binding of the membrane-bound FASL to its receptor triggers clustering of the receptors and formation of the death-inducing signaling complex, DISC, which constitutes of FADD and procaspase-8 [21]. Caspase-8 processes the BH3-only protein BH3 interacting domain death agonist (BID) into its active form tBID (p15) and thereby amplifies the caspase activation cascade by engaging the intrinsic, called mitochondrial, apoptotic pathway [22,23]
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