Editors' ChoiceInnate Immunity

Unexpected Inhibition

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Sci. Signal.  22 Mar 2011:
Vol. 4, Issue 165, pp. ec86
DOI: 10.1126/scisignal.4165ec86

Nuclear factor κB (NF-κB) plays an important role in innate immunity in many animals, where it regulates expression of genes involved in the response to pathogens. In Drosophila melanogaster, activation of the NF-κB homolog Relish (Rel) can be induced by signaling through either the Toll or IMD (immune deficiency) pathway. IMD is an adaptor protein that mediates the interaction of PGRP-LC, a receptor for bacterially derived peptidoglycans, with downstream components leading to Rel activation. Ragab et al. report that signaling through the Ras-MAPK (mitogen-activated protein kinase) cascade suppresses IMD signaling to fine-tune the immune response. In cultured Drosophila SL2 cells, decreasing Ras-MAPK signaling by RNA interference (RNAi) increased the IMD response to Gram-negative bacteria, whereas increasing MAPK signaling decreased the IMD response. In contrast, manipulating Ras-MAPK signaling had no effect on Toll signaling. RNAi of Ras-MAPK signaling components led to induction of IMD targets even in the absence of bacterial stimulation, implying that Ras-MAPK signaling was required for basal repression of IMD signaling. Similarly, increasing Ras-MAPK signaling in bacterially infected larvae repressed expression of an IMD-induced antimicrobial peptide (AMP) in the fat body, a liver-like metabolic and secretory organ, and in the macrophage-like hemocytes but had no effect on expression of a Toll-induced AMP. Adult flies with increased Ras-MAPK signaling exhibited decreased survival after septic injury but no change in survival after infection with a fungus that primarily elicits a Toll-dependent immune response. Ras-MAPK signaling also played a role in modulating IMD signaling in intestinal immunity in adults, where it was required for stem cell proliferation. Finally, the authors demonstrated that Ras-MAPK signaling likely inhibited IMD signaling by inducing the expression of Pirk, a protein that prevents IMD from binding to PGRP-LC. Ras-MAPK signaling thus limits IMD signaling during infection and prevents activation of IMD target genes in the absence of pathogen. Given that many Drosophila immune regulation pathways are conserved in mammalian innate immunity, these findings may be relevant to overactivation of the innate immune response in humans, which leads to chronic inflammation, a condition associated with obesity and cancer.

A. Ragab, T. Buechling, V. Gesellchen, K. Spirohn, A.-L. Boettcher, M. Boutros, Drosophila Ras/MAPK signalling regulates innate immune responses in immune and intestinal stem cells. EMBO J. 30, 1123–1136 (2011). [PubMed]

K.-Z. Lee, D. Ferrandon, Negative regulation of immune responses on the fly. EMBO J. 30, 988–990 (2011). [PubMed]

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