Be a Good Neighbor: Organ-to-Organ Communication during the Innate Immune Response
Authors: Alla Amcheslavsky, Y. Tony Ip
Journal: Cell Host & Microbe (2012)

Local infection in the Drosophila larval intestine elicits a systemic immune reaction in fat bodies. In this issue, Wu et al., 2012Wu S.C. Liao C.W. Pan R.L. Juang J.L. Cell Host Microbe. 2012; 11 (this issue): 410-417Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar show that this is a reactive oxygen species-dependent communication. Local infection in the Drosophila larval intestine elicits a systemic immune reaction in fat bodies. In this issue, Wu et al., 2012Wu S.C. Liao C.W. Pan R.L. Juang J.L. Cell Host Microbe. 2012; 11 (this issue): 410-417Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar show that this is a reactive oxygen species-dependent communication. For an organism to function effectively under varying environmental conditions, its physiological systems must communicate and adapt coordinately to maintain an optimal or steady state. Interorgan communication, including immunological crosstalk, helps one organ adjust its performance based on another organ's response to physiological or pathological changes (Rajan and Perrimon, 2011Rajan A. Perrimon N. Dev. Cell. 2011; 21: 29-31Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). The underlying mechanism for this continuous communication and adjustment in the whole animal, referred to as homeostasis, is understandably complex, and much remains to be explored. The Drosophila gut provides a very useful model to study the integration of host-microbe interaction, immunity, and regeneration. Drosophila does not have an adaptive immune system, and its self-defense relies solely on the innate immune response (Ferrandon et al., 2007Ferrandon D. Imler J.L. Hetru C. Hoffmann J.A. Nat. Rev. Immunol. 2007; 7: 862-874Crossref PubMed Scopus (639) Google Scholar). Like in other metazoans, the gut epithelium in insects is the first line of defense against ingested pathogens. The gut functions as a physical barrier, but also produces antimicrobial peptides (AMPs) and reactive oxygen species (ROS) to curb the initial microbial titers. If microorganisms break through the gut epithelium and enter the hemolymph, the blood equivalence in insects, specialized hemocytes participate in phagocytosis and encapsulation of the invaders. Finally, the fat body is both a fat depot and a factory for AMP and growth factor production, and therefore it functions as the main tissue for the humoral and systemic response. However, the interactions among the gut, hemocytes, and fat body have not been explored extensively. The study by Wu et al., 2012Wu S.C. Liao C.W. Pan R.L. Juang J.L. Cell Host Microbe. 2012; 11 (this issue): 410-417Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar demonstrates how gut infection, oxidizing chemicals, and genetic manipulations trigger the intestine to induce an innate immune response in the fat body. The phytopathogenic bacteria Ecc15 is pathogenic to plants such as carrot, but is not pathogenic to Drosophila, although it can grow in a fly gut. Feeding of Ecc15 to larvae increases the expression of AMPs within the gut and thereby stimulates host defense. Interestingly, Ecc15 also stimulates the expression of AMPs in another organ that it does not infect, the fat body (Basset et al., 2000Basset A. Khush R.S. Braun A. Gardan L. Boccard F. Hoffmann J.A. Lemaitre B. Proc. Natl. Acad. Sci. USA. 2000; 97: 3376-3381Crossref PubMed Scopus (283) Google Scholar, Foley and O'Farrell, 2003Foley E. O'Farrell P.H. Genes Dev. 2003; 17: 115-125Crossref PubMed Scopus (216) Google Scholar). What is the underlying mechanism for this phenomenon? The fat body is a presumably freestanding tissue not connected with the gastrointestinal tract, even though they are the two main organs that bathe in the hemolymph and occupy most of the larval body cavity. Ecc15 is not detectable in the hemolymph after ingestion by the larvae, and therefore it is not likely that the bacteria break through the gut epithelium to interact with the fat body directly. A logical postulation is that the gut sends a signal to other organs after enteric infection (Figure 1). This reaction in distant tissues/organs in response to local infection may prepare the host for full protection, such as clearing the remaining pathogens and optimizing tissue repair. In the report, Wu et al. improve this interorgan communication model to a great extent by showing that the homeostatic interplay between intestinal ROS and nitric oxide (NO) regulates fat body expression of the AMP diptericin through a mechanism that requires the NF-κB protein Relish. ROS have been shown to be highly efficient immune effector molecules and exert broad spectrum microbicidal activity in clearing microbes from the gut (Ha et al., 2005Ha E.M. Oh C.T. Bae Y.S. Lee W.J. Science. 2005; 310: 847-850Crossref PubMed Scopus (581) Google Scholar). Although intestinal ROS have long been recognized for their roles in the onset of inflammatory bowel disease (Rezaie et al., 2007Rezaie A. Parker R.D. Abdollahi M. Dig. Dis. Sci. 2007; 52: 2015-2021Crossref PubMed Scopus (470) Google Scholar), it remains largely unknown whether intestinal ROS also trigger interorgan immunological communication. Wu et al. clearly demonstrate that ROS is critical in the gut to communicate with the fat body. ROS production after infection triggers NO production in the gut that in turn regulates fat body diptericin expression. These results are highly consistent with a previous report showing that ingestion of a NO donor in larvae triggered AMP responses in the fat body (Foley and O'Farrell, 2003Foley E. O'Farrell P.H. Genes Dev. 2003; 17: 115-125Crossref PubMed Scopus (216) Google Scholar). In addition, Wu et al. show that there is also feedback inhibition of NO to ROS, suggesting a complex interplay. Despite the demonstrated involvement of ROS and NO in the gut-to-fat body communication, there is still an additional mystery, which is that ROS is short lived. ROS is destructive to both microbes and host cells, and its release and action have to be transient. What, then, relays the signal of ROS induced in the gut to the response in the fat body? Many researchers are still puzzled by the identity of possible messengers that make interorgan communication possible. Hemocytes are clearly important for this process, because mutants lacking hemocytes do not have a response in the fat body after gut infection. Wu et al. tested the JAK-STAT pathway and its ligand Unpaired 3 (Upd3) as part of the mechanisms. Upd3 was first identified as a cytokine expressed in hemocytes after septic injury and necessary for the JAK/STAT-dependent activation of the stress gene totA in the fat body (Agaisse et al., 2003Agaisse H. Petersen U.M. Boutros M. Mathey-Prevot B. Perrimon N. Dev. Cell. 2003; 5: 441-450Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). Furthermore, a number of recent papers show that the Unpaired family of ligands, including Upd3, are produced in the gut after infection or stress, and they are probably required to promote regeneration (Jiang et al., 2009Jiang H. Patel P.H. Kohlmaier A. Grenley M.O. McEwen D.G. Edgar B.A. Cell. 2009; 137: 1343-1355Abstract Full Text Full Text PDF PubMed Scopus (698) Google Scholar). Wu et al. show that Upd3 is indeed produced in the infected gut, but when they examined the function of JAK-STAT signaling in the fat body, it appeared to act as a repressor for AMP genes. All these results suggest a complex role of the Unpaired-JAK-STAT signaling in interorgan communication (Basset et al., 2000Basset A. Khush R.S. Braun A. Gardan L. Boccard F. Hoffmann J.A. Lemaitre B. Proc. Natl. Acad. Sci. USA. 2000; 97: 3376-3381Crossref PubMed Scopus (283) Google Scholar, Foley and O'Farrell, 2003Foley E. O'Farrell P.H. Genes Dev. 2003; 17: 115-125Crossref PubMed Scopus (216) Google Scholar, Wu et al., 2012Wu S.C. Liao C.W. Pan R.L. Juang J.L. Cell Host Microbe. 2012; 11 (this issue): 410-417Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Overall, it is worth further investigating whether Upd3 is a second messenger and the role of JAK-STAT in directing organ-organ communication. First, loss-of-function analysis of Upd3 either by RNAi or a mutant in the gut, hemocytes, or whole body should give a better understanding of the role of the ligand in this process. Second, the JAK-STAT pathway in the fat body can activate totA but repress diptericin gene expression. Therefore, the pathway can be studied from a different angle, such as using different Upd ligands, concentrations, or mutant alleles that may yield different outcomes. Third, it is still not clear whether hemocytes function as an obligate middle organ or as a coactivator to stimulate the fat body response. Clarifying the role of hemocytes may help to define how the messengers work. There are likely other second messengers involved in gut-to-fat body communication. Although ROS are supposed to be short lived, some ROS may diffuse into the hemolymph and act as messengers. Another consideration is that even though the Ecc15 bacteria may not penetrate the gut epithelium, we cannot exclude the possibility that bacterial components are involved. Upon intestinal infection of the more pathogenic bacteria P. entomophila, peptidoglycan fragments can cross the gut barrier into the hemolymph and subsequently trigger a systemic immune response in the fat body (Zaidman-Rémy et al., 2006Zaidman-Rémy A. Hervé M. Poidevin M. Pili-Floury S. Kim M.S. Blanot D. Oh B.H. Ueda R. Mengin-Lecreulx D. Lemaitre B. Immunity. 2006; 24: 463-473Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar). Ecc15, however, may not be virulent enough to cause tissue damage, and therefore the fat body response still likely requires second messenger secretion from gut cells. To look for these messengers, the sophisticated tools available in Drosophila, e.g., knockdown genes in the gut or fat body separately, should be helpful. However, an adverse scenario is that multiple second messengers are involved, and simple genetic screens will not be able to identify them one at a time. The fat body as a response tissue expresses more AMPs, presumably for systemic protection after local infection. Based on their results, Wu et al. propose that ROS-NO interplay in the gut contributes to a tight regulation of AP-1, a transcription factor that normally suppresses Relish/NF-κB-dependent AMP expression in fat bodies. These findings allow additional ways to investigate organ-to-organ communication. One is to examine how AP-1 and Relish are regulated in the fat body after gut infection. The PGRP-LC/IMD innate immune signaling pathway that regulates Relish during systemic infection is well characterized. Whether this same pathway plays a role during gut-to-fat communication is an interesting question. Similarly, for AP-1, investigating the MAP kinase signaling pathway and receptor tyrosine kinases may provide insight into the coordinated response in the whole animal. Y.T.I. is supported by a grant from NIH-NIDDK (DK83450) and is a member of the UMMS Diabetes Endocrinology Research Center supported by NIH-NIDDK (DK32520). Infection-Induced Intestinal Oxidative Stress Triggers Organ-to-Organ Immunological Communication in DrosophilaWu et al.Cell Host & MicrobeApril 19, 2012In BriefLocal infections can trigger immune responses in distant organs, and this interorgan immunological crosstalk helps maintain immune homeostasis. We find that enterobacterial infection or chemically and genetically stimulating reactive oxygen species (ROS)-induced stress responses in the Drosophila gut triggers global antimicrobial peptide (AMP) responses in the fat body, a major immune organ in flies. ROS stress induces nitric oxide (NO) production in the gut, which triggers production of the AMP Diptericin, but not Drosomycin, in the fat body. Full-Text PDF Open Archive