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    • Treatment of recipients with the pro inflammatory

    2018-10-23

    Treatment of recipients with the pro-inflammatory PAMP, poly(I:C), prior to fresh HOD RBC transfusion resulted in alloantibody production comparable to the response to stored RBCs (Fig. 1e). It should be noted that this study did not directly address whether the demonstrated pro-inflammatory cytokine response to transfused stored HOD RBCs was necessary for alloimmunization. However, multiple studies in mice and humans have reported associations between inflammatory states and alloimmunization (Ramsey and Smietana, 1995; Fasano et al., 2015; Papay et al., 2012; Yazer et al., 2009; Hendrickson et al., 2006; Ryder et al., 2015). Additionally, it is firmly accepted that innate inflammatory responses can promote APC activation and adaptive immune responses (Iwasaki and Medzhitov, 2010). Although many APC cell types consume transfused RBCs in the spleen (Richards et al., 2016), we have demonstrated that splenic cDCs critically regulate the alloantibody response to stored HOD RBCs in a T cell-dependent manner (Calabro et al., 2016). We also observed that stored RBCs induce cDC activation, independent of HOD expression. However, it is not clear whether stored RBC DAMPs are directly recognized by cDCs. PRR activation in CD11b+Ly6C+F4/80+ macrophages, shown to consume stored RBCs (Calabro et al., 2016), may instead cause production of pro-inflammatory cytokines that activate cDCs and promote cDC phagocytic activity. Such an indirect mechanism is supported by a prior study reporting that clodronate-induced macrophage depletion abrogates MCP-1 and KC production following transfusion of stored RBCs (Wojczyk et al., 2014). Regardless, these findings suggest that cDC activation may critically regulate the alloimmune response. Yet, the lysophosphatidic acid process for cDC activation has not been defined. To address this challenge, we took advantage of the discrete nature of PRR:DAMP interactions. Thus, identifying a PRR pathway that regulates alloimmunization will greatly narrow the search for relevant immunomodulatory DAMPs in stored RBCs. It also has the potential to identify downstream cytokine profiles associated with alloimmunization. Although numerous PRRs could be tested, NLRP3 and other inflammasome-forming NLRs were excellent candidates. NLRP3 is activated by numerous DAMPs, including protein aggregates, insoluble crystals, and products of cell death (Krishnaswamy et al., 2013) (Guo et al., 2015; Storek and Monack, 2015). With regards to potential RBC DAMPs, NLRP3 inflammasomes are activated by ATP (Mariathasan et al., 2006), which is released from damaged RBCs (Dern et al., 1967), and iron-containing heme (Dutra et al., 2014), which can be produced by intracellular catabolism of phagocytosed RBCs (Hod et al., 2010). In addition, reactive oxygen species, which prime NLRP3 activation (Juliana et al., 2012), were implicated in stored HOD RBC-induced inflammation, which was reduced by anti-oxidant treatment (Hod et al., 2010). Nonetheless, the lack of NLRP3 or associated caspase-1 or caspase-11 had no significant effect on stored RBC-induced inflammatory and alloimmune responses. This finding was supported by alloimmune responses of Il1rxIl18−/− mice that were comparable to WT responses. We cannot exclude the possibility that NLR-forming inflammasomes could perform more significant roles in response to storage of RBCs expressing other antigens, not tested in this study. We believe this possibility is unlikely given our findings that the nature of the alloantigen on the stored RBCs did not impact DC activation. Although not examined in this study, other PRRs, including TLRs and Rig-I-like receptors (RLRs), may regulate responses to stored RBCs. Even though TLRs and RLRs primarily recognize foreign PAMPs, they can also recognize certain DAMPs, including self-nucleic acids and intracellular molecules released during cell death (Piccinini and Midwood, 2010). Red blood cells are not nucleated, yet the washed leuko-reduced RBC preparations contain reticulocytes, platelets, and a low level of leukocytes (Ryder et al., 2014) that may release TLR ligands during storage. Future studies examining inflammatory and adaptive immune responses of various PRR-deficient mice to different RBC preparations may lead to progress in identifying DAMPs associated with alloimmunization. Indeed, identification of a potential DAMP endogenous to RBCs themselves or to the RBC product preparation could redefine transfusion practices.