Ribosomal protein S19 is a novel therapeutic agent in inflammatory kidney disease

Abstract

RPS19 (ribosomal protein S19), a component of the 40S small ribosomal subunit, has recently been identified to bind the pro-inflammatory cytokine macrophage MIF (migration inhibitory factor). In vitro experiments identify RPS19 as the first endogenous MIF inhibitor by blocking the binding of MIF to its receptor CD74 and MIF functions on monocyte adherence to endothelial cells. In the present study, we sought to establish whether recombinant RPS19 can exert anti-inflammatory effects in a mouse model of anti-GBM (glomerular basement membrane) GN (glomerulonephritis) in which MIF is known to play an important role. Accelerated anti-GBM GN was induced in C57BL/6J mice by immunization with sheep IgG followed 5 days later by administration of sheep anti-mouse GBM serum. Groups of eight mice were treated once daily by intraperitoneal injection with 6 mg of RPS19/kg of body weight or an irrelevant control protein (human secretoglobin 2A1), or received no treatment, from day 0 until being killed on day 10. Mice that received control or no treatment developed severe crescentic anti-GBM disease on day 10 with increased serum creatinine, declined creatinine clearance and increased proteinuria. These changes were associated with up-regulation of MIF and its receptor CD74 activation of ERK (extracellular-signal-regulated kinase) and NF-κB (nuclear factor κB) signalling, prominent macrophage and T-cell infiltration, as well as up-regulation of Th1 [T-bet and IFNγ (interferon γ)] and Th17 [STAT3 (signal transducer and activator of transcription 3) and IL (interleukin)-17A] as well as IL-1β and TNFα (tumour necrosis factor α). In contrast, RPS19 treatment largely prevented the development of glomerular crescents and glomerular necrosis, and prevented renal dysfunction and proteinuria (all P<0.001). Of note, RPS19 blocked up-regulation of MIF and CD74 and inactivated ERK and NF-κB signalling, thereby inhibiting macrophage and T-cell infiltration, Th1 and Th17 responses and up-regulation of pro-inflammatory cytokines (all P<0.01). These results demonstrate that RPS19 is a potent anti-inflammatory agent, which appears to work primarily by inhibiting MIF signalling.

A 24-48 h fed Amblyomma americanum tick saliva immuno-proteome

“…Ribosomal proteins function is predominantly intracellular, but several studies have described extracellular functions of ribosomal proteins in mammals exerting anti-inflammatory activity [223–225]. One of the most studied, ribosomal protein S19 was recently shown to bind the pro-inflammatory cytokines [224]. Whether or not A. americanum putative S19 protein (GBAI01000085, GBAJ01000004, and GBAK01000158) will functionally bind pro-inflammatory cytokines remains to be investigated.…”

Identification of 24h Ixodes scapularis immunogenic tick saliva proteins

“…The high prevalence of ribosomal proteins is intriguing and could indicate that they serve as more than simple housekeeping functions in ticks. Additional functions of ribosomal proteins have become evident, including anti-inflammatory activity (Abreu-Velez et al, 2013; Lv et al, 2013; Poddar et al, 2013). GBSR01000004 and GBSR01000006, respectively have 77% and 71% identity to two separate ribosomal proteins in Ailuropoda melanoleuca which have each been characterized and shown anti-cancer function by inhibiting cell growth and proliferation activity (Li et al, 2014; Su et al, 2012).…”

Active regulator of SIRT1 is required for ribosome biogenesis and function

“…RPS19 has been implicated in the suppression of inflammation, either via formation of a post-apoptotic covalent dimer, which acts as a suppressor of acute inflammation (48), or via inhibition of the pro-inflammatory cytokine MIF (macrophage migration inhibitory factor) (49,50). Furthermore, RPS19 may play a role in an infectious disease; direct interaction between RPS19 and the hantavirus nucleocapsid protein is believed to subvert translation towards viral transcripts (51).…”