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  • br Conflicts of interest br

    2020-11-20


    Conflicts of interest
    Financial support NZ is an Established Investigator of the Dutch Heart Foundation (2013T111) and is supported by an ERC Consolidator grant (617376) from the European Research Council and by a Vici grant from the Netherlands Organization for Scientific Research (NWO; 91818643). AL is supported by a Dekker grant from the Dutch Heart Foundation (2016T015). JT is supported by an AMC PhD fellowship.
    Author contributions
    Acknowledgments
    Introduction Sepsis is a bi-phasic disease characterized by an initial hyper-inflammatory phase called systemic inflammatory response syndrome (SIRS), which is followed by an immune compromised phase called endotoxin tolerance (ET) (Biswas and Lopez-Collazo, 2009). The SIRS phase is marked by the drastic production of pro-inflammatory cytokines and downregulation of anti-inflammatory cytokines, whereas the opposite occurs during the ET phase (Cavaillon and Adib-Conquy, 2006). In SIRS, the inflammatory insult leads to impaired blood vessel contractility and reduced cardiac index, resulting in circulatory failure (Ren and Wu, 2006). Persistent circulatory failure leads to rupturing of the microcirculatory vasculature, a major determinant of mortality in sepsis (Levi et al., 2010). A recent study reveals a protective role for interferon regulatory factor 3 (IRF3)-dependent IFN-β production in lethal LPS endotoxin-mediated sepsis by controlling the Isochlorogenic acid B of silent information regulator transcript-1 (SIRT1) in murine bone-marrow-derived macrophages (BMDMs) (Yoo et al., 2014). Previous studies also highlight the importance of macrophage polarization (Biswas and Lopez-Collazo, 2009) and ubiquitin-proteasome pathways (Wray et al., 2003) during sepsis, but the molecular mechanisms underlying these processes and the regulation of the switch from SIRS to ET requires more investigation. Ubiquitin modification and its role in the crosstalk between proteins has been studied for the past few decades, but its role in immune response signaling is rather recent. The role of ubiquitin modification in activating or repressing protein function has recently been reported during TLR signaling mediated by the nuclear factor κB (NF-κB) and interferon type 1 (IFN-I) pathways (Heaton et al., 2016), but its regulation remains uncharacterized. Downstream signaling from TLRs is mediated by either the MyD88-TIRAP or TRIF-TRAM pathway. Among all the TLRs, only LPS-activated TLR4 can induce both MyD88- and TRIF-dependent signaling (Kagan et al., 2008). It does this by mediating MyD88-dependent responses from the cell surface and TRIF-dependent responses when internalized into endosomes (Tanimura et al., 2008). Recent research has uncovered a possible role for the polyubiquitination of cellular inhibitor of apoptosis 1/ 2 (cIAP1/2) and TNF receptor associated factor 3 and 6 (TRAF3 and TRAF6) (Tseng et al., 2010) in mediating the shift from MyD88- to TRIF-dependent signaling and subsequent IFN-I production in BMDMs. Studies have also shown that endocytosis of TLR4 in BMDMs is critically dependent on the phosphorylation of spleen tyrosine kinase (SYK) and phospholipase C gamma 2 (PLCγ2) (Zanoni et al., 2011). How these proteins regulate TLR4 endocytosis during the shift between these two pathways still remains elusive. Prior research has identified the upregulation of ABCF1, in TNF-α-stimulated synoviocytes from rheumatoid arthritis patients (Richard et al., 1998). While retaining its ATP-binding cassette, ABCF1 is unusual as it lacks a transmembrane domain and does not function as a transporter. ABCF1 is thought to aid in translation initiation and is located in the cytoplasm and nucleoplasm (Paytubi et al., 2008). Immunological studies have shown that ABCF1 is also involved in innate immune cytosolic DNA sensing mechanisms (Lee et al., 2013) and has been linked to susceptibility for autoimmune pancreatitis (Ota et al., 2007). Due to the embryonic lethality of ABCF1-deficient mice (Abcf1), we created an ABCF1 heterozygous mouse (Het; Abcf1+/−) and studied its promoter activity during embryonic development and in various adult tissues (Wilcox et al., 2017). However, despite these studies, the molecular functions and physiological role of ABCF1 remains elusive.