Title:
Extra-Ribosomal Functions of Ribosomal Protein S19: Increment of Neutrophil Influx in Gln137Glu Mutant Ribosomal Protein S19 Knocked-In C57BL/6J Heterozygous Mice
Hiroshi Nishiura: Assistant professor
Department of Molecular Pathology, Faculty of Life Science, Kumamoto University , Kumamoto , Japan
Abstract:
The traditional view is that one ligand binds to only one receptor. The gene structure of the fifth complement component C5a receptor (C5aR) indicates no splice valiant of its mRNA. 1 Mice deficient in C5aR ligand pre-form C5 commonly exhibits a reduction of neutrophil influx during acute inflammation. 2, 3 On the other hand, programmed cell death process of human neutrophilsin vitro is extended by a simultaneous presence of C5a. 4 Therefore, they believe that one of G protein-coupled receptors C5aR on neutrophils is crucial for anti-apoptosis and pro-inflammation at the initiation phase in acute inflammation.
Paradoxically, two reports have shown that C5aR-deficient mice show opposing neutrophil responses, with an increment of neutrophil influx seen in Pseudomonas aeruginosa -induced bronchopneumonia and a reduction of neutrophil influx seen in the anti-ovalbumin rabbit IgG-induced reverse passive Arthus model. 5, 6 Moreover, a blockade of the C5aR function by a C5aR antagonistic peptide (PMX-53: Ac-Phe-[Orn-Pro-dCha-Trp-Arg]) 7 results in an inhibition of carra geen a n – and lipopolysaccharide -induced rat hypernociception without a reduction of neutrophil influx. 8 These data suggest that more than one ligand exists for pro-apoptosis and anti-inflammation via the neutrophil C5aR.
We know that monocyte influx is commonly increased in chronic inflammation, such as Rheumatoid Arthritis-synovium. To study this mechanism, we prepared synovial tissue extracts and identify ribosomal protein S19 (RP S19) dimer as a monocyte specific chemoattrantant. 9 RP S19 monomers in ribosome move to phosphatidylserine during apoptosis and are cross-linked between Lys122 and Gln137 by tissue transglutaminases. 10 The cross-linked RP S19 dimer released from apoptotic cells exhibits pro-apoptosis and chemotaxis effects on neutrophils and monocytes/macrophages via the C5aR, respectively.
We recently found that programmed cell death process of human neutrophils in vitro is extended by a simultaneous presence of neutralizing antibodies against the RP S19 dimer, anti-human C5a rabbit IgG, or of PMX-53. 11 Moreover, neutrophil influx in Crlj:CD1 mouse acute pleurisy is increased by an administration of anti-human C5a rabbit IgG for 24 hrs post carra geen a n- injection. This is reproduced i n Gln137Glu mutant RP S19 knocked-in C57BL/6J heterozygous mice. We demonstrate that the RP S19 dimer released from the infiltrating neutrophils synchronizes pro-apoptosis of the infiltrating neutrophils and attraction of monocytes/macrophages via the C5aRs at the resolution phase in acute inflammation.
References:
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