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2013/05/30 M2 Yuki Maruyama Toll/Imd pathways link to insects cellular immune response via eicosanoid biosynthesis Insects utilize innate immune response exclusively which are divided into humoral and cellular reaction. Humoral immunity contains antimicrobial peptides (AMPs) systhesis and plasma melanization by phenoloxidase (PO) activity. Cellular immunity contains phagocytosis, nodule formation and encapsulation. Nowadays, in terms of humoral reaction, the molecular mechanisms of the activation against infection are well known, for example, Toll/Imd pathways to synthesize AMPs. Though both Toll and Imd pathways regulate expression of AMPs, the one responds to gram positive bacteria and fungi, the other responds to gram negative bacteria respectively. However, there is little understanding about the molecular mechanisms of cellular reaction. Eicosanoids are the oxygenated metabolites of biologically active C20 polyunsaturated fatty acids from arachidonic acid which is a catalytic product of phospholipid by phospholipase A₂ (PLA₂). Eicosanoids have been reported to play key roles in insect immunity (Stanley. 2011). This paper reviews that Toll/Imd pathways not only regulate humoral reaction, but also link functionally to cellular reaction against bacterial challenge via eicosanoid synthesis. Eicosanoids mediate various cellular immune responses such as phagocytosis and nodule formation (Shrestha and Kim. 2009), additionally, hemocyte spreading (Mandato et al.1997) and encapusulation (Carton. 2002) in insects. Eicosanoid biosynthesis is induced by bacterial or fungal infection because it has been reported that the activity of PLA₂ increased after injection of E. coli in Drosophila (Yajima et al. 2003) and Beauveria bassiana in S. exigua (Park and Kim. 2012). Eicosanoids also mediate humoral immune response such as induction of AMPs synthesis. It has been showed eicosanoid biosynthesis inhibitor inhibited expression of AMPs (Morishima et al. 1997) and Imd signal pathway is inhibited by eicosanoid biosynthesis inhibitor (Yajima et al. 2003). Accordingly, the possibility of interaction between eicosanoids and Toll/Imd pathways has been predicted. This hypothesis has been verified by RNA interference (RNAi) in some insects. In red flour beetle, Tribolium castaneum infected by gram negative or positive bacteria after injection of dsRNA specific to four Toll receptor genes and Imd related gene resulted in suppression of PLA₂ activities and suppression of PLA₂ gene expression (Shretha and Kim. 2010). Additionally, in Spodoptera exigua , RNAi using dsRNA specific to Toll receptor gene also suppressed PLA₂ activity induced by Beauveria bassiana injection (Park and Kim. 2012). Moreover, same paper showed that Toll signal activates cellular reaction via eicosanoids. Though the number of nodule formation of B. bassiana by S. exigua hemocytes reduced in response to dsRNA specific to Toll injection, the reduction effect was rescued by addition of arachidonic acid (AA), intermediates of eicosanoids. In recent years, it has been reported that plasmatocyte spreading peptide (PSP) which induce spreading of plasmatocyte and oenocytoid cell lysis (OCL) plays a role of intermediator between Toll pathway and eicosanoids biosynthesis in S. exigua (Park and Kim. 2012). Suppression of PSP gene expression by RNAi resulted in reduction of PLA₂ activity. The report that eicosanoids induce OCL (Mandato et al. 1997) and the evaluation of OCL rates and PO activity induced by PSP revealed that PSP mediates eicosanoid biosynthesis. Injection of dsRNA specific to Toll gene suppressed PSP gene expression. This fact suggests that PSP signal is under Toll. According to OCL experiment, the number of oenocytoids which decrease in response to PSP induced by B. bassiana significantly prevented to decrease by knockdown of Toll expression. Furthermore, an addition of dexamethasone which has inhibitory effect on PLA₂ inhibited OCL although an addition of PSP to the RNAi-treated larvae recovered the response. This study showed that PSP was dependent on eicosanoids to activate OCL induction because it significantly enhanced PLA₂ activities, and because an addition of PLA₂ inhibitor significantly inhibited PSP effect. Thus, it appears that eicosanoids which induce various cellular immune response are regulated by Toll/Imd pathway at least moieties. And in terms of S. exigua, it is probably considered that PSP expression may be up-regulated by Toll pathway after fungal infection. The increased PSP transcripts would be translated and secreted to plasma. The PSP in the plasma may bind to its specific receptor on the target cell membrane and subsequent intracellular PSP signal would activate PLA₂ and eventually biosynthesized eicosanoids. This review “partially” shows the activation mechanism of cellular immune response. However, because there is little understanding detailed mechanism, further studies have been required. References 1. Shrestha S, Kim Y (2009) Various Eicosanoids Modulate the Cellular and Humoral Immune Responses of the Beet Armyworm, Spodoptera exigua. Biosci. Biotechnol. Biochem. 73:2077-2084 2. Yajima M, Takada M, Takahashi N, Kikuchi H, Natori S, Oshima Y, Kurata S (2003) Anewly established in vitro culture using transgenic Drosophila reveals functional coupling between the phospholipase A₂-generated fatty acid cascade and lipopolysaccharide-dependent activation of the immune deficiency (imd) pathway in insect immunity. Biochem. J. 371:205-210 3. Park JA, Kim Y (2012) Eicosanoid biosynthesis is activated via Toll, but not Imd signal pathway in response to fungal infection. Journal of Invertebrate Pathology 110: 382-388 4. Shrestha S, Kim Y (2010) Activation of immune-associated phospholipase A₂ is functionally linked to Toll/Imd signal pathways in the red flour beetle, Tribolium castaneum. Developmental and Comparative Immunology 34: 530-537 5. Park JA, Kim Y (2012) Toll recognition signal activates oenocytoid cell lysis via a crosstalk between plasmatocyte-spreading peptide and eicosanoids in response to a fungal infection. Cellular Immunology 279: 117-123 6. Stanley D, Miller J, Tunaz H (2009) Eicosanoid Actions in Insect Immunity. J innate Immun 1: 282-290 7. Stanley D, Miller J (2006) Eicosanoid actions in insect cellular immune functions. Entomologia Experimenttalis et Applicata 119: 1-13 Key words Cellular immunity, Toll/Imd pathway, Eicosanoid biosynthesis, phospholipase A₂ (PLA₂), plasmatocyte spreading peptide (PSP)