A shortcut mechanism of innate immune defense by a solitary PRR
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1
National University of Singapore, Biological Sciences, Singapore
The accepted paradigm about an innate immune response is a multi-stepped process - from recognition of the invading microbe by pathogen-recognition receptors (PRRs) to signal transduction, to the production of antimicrobial effectors by the immune cells. Contrary to this belief, we found that a PRR can act singly via a direct shortcut process, bypassing multiple cascades of reactions. We showed that the extracellular hemoglobin (Hb) acts as a solitary frontline defense PRR, directly recognizing pathogens and eliciting powerful antimicrobial potencies. This innate immune response phenomenon is evolutionarily entrenched for 500 million years, from the limulus to humans. While the invading microbe cleaves the cell-free hemoglobin to extract an iron-rich meal for its survival and further invasion, the host exploits the intruding microbe’s proteases and PAMPs to produce toxic reactive oxygen species (ROS) that effectively kills the pathogen. In this process, the hemoglobin structure-function is rapidly reprogrammed to expose multiple dual antimicrobial activities and its redox reactivity is subsequently suppressed by plasma antioxidants, thus protecting the host from ROS-induced cytotoxicity. Furthermore, we demonstrated that the monocytes efficiently import the redox active Hb via a (a) novel endocrine loop of CD163 receptor recycling and (b) paracrine communication with vascular endothelial cells.
Acknowledgements
We thank the MoE and A*STAR BMRC for financial support.
References
Jiang N, Tan NS, Ho B and Ding JL. Respiratory protein-generated reactive oxygen species as an antimicrobial strategy. Nature Immunology 8 (2007): 1114-1122
Du RJ, Ho B and Ding JL. Rapid reprogramming of haemoglobin structure-function exposes multiple dual-antimicrobial potencies. EMBO J 29 (2010): 632-642
Bahl N, Du R, Winarsih I, Ho B, Tucker-Kellogg L, Ho B and Ding JL. Delineation of LPS-binding sites of hemoglobin - from in silico predictions to biophysical characterization. J. Biol. Chem 286 (2011): 37793-37803.
Du R, Winarsih I, Ho B and Ding JL. Lipid-free apolipoprotein A1 exerts an antioxidative role against cell-free hemoglobin. Am. J. Clin. Exp. Immunol. 1 (2012): 33-48.
Subramanian K, Du RJ, Tan NS, Ho B and Ding JL. CD163 and IgG co-defend against cytotoxic hemoglobin via autocrine and paracrine mechanisms. J. Immunol. (in press)
Keywords:
Innate immune defense,
Pathogen pattern-recognition receptors (PRRs),
Hemoglobin,
Reactive Oxygen Species,
Host-Pathogen Interactions
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Innate immunity
Citation:
Ding
J
(2013). A shortcut mechanism of innate immune defense by a solitary PRR.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00433
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Received:
02 Apr 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Jeak Ling Ding, National University of Singapore, Biological Sciences, Singapore, 117543, Singapore, dbsdjl@nus.edu.sg