Intravesical CD74 and CXCR4, macrophage migration inhibitory factor (MIF) receptors, mediate bladder pain

Abstract

Background Activation of intravesical protease activated receptor 4 (PAR4) leads to release of urothelial macrophage migration inhibitory factor (MIF). MIF then binds to urothelial MIF receptors to release urothelial high mobility group box-1 (HMGB1) and elicit bladder hyperalgesia. Since MIF binds to multiple receptors, we investigated the contribution of individual urothelial MIF receptors to PAR4-induced HMGB1 release in vivo and in vitro and bladder pain in vivo. Methodology/Principal findings We tested the effect of intravesical pre-treatment with individual MIF or MIF receptor (CD74, CXCR4, CXCR2) antagonists on PAR4-induced HMGB1 release in vivo (female C57/BL6 mice) and in vitro (primary human urothelial cells) and on PAR4-induced bladder hyperalgesia in vivo (mice). In mice, PAR4 induced HMGB1 release and bladder hyperalgesia through activation of intravesical MIF receptors, CD74 and CXCR4. CXCR2 was not involved in these effects. In primary urothelial cells, PAR4-induced HMGB1 release through activation of CD74 receptors. Micturition parameters in mice were not changed by any of the treatments. Conclusions/Significance Urothelial MIF receptors CD74 and CXCR4 mediate bladder pain through release of urothelial HMGB1. This mechanism may set up persistent pain loops in the bladder and warrants further investigation. Urothelial CD74 and CXCR4 may provide novel targets for interrupting bladder pain.

Single-cell transcriptome landscape of zebrafish liver reveals hepatocytes and immune cell interactions in understanding nonalcoholic fatty liver disease

“…Marco ( 40 ), cxcl8a ( 41 ) and csf1ra ( 42 ) were highly expressed in noninflammatory macrophages, while grn1 ( 43 ), mpeg1 . 1 ( 44 ) and cxcr4b ( 45 ) were predominantly expressed in inflammatory macrophages. Additionally, pax5 ( 46 ) and cd79a ( 47 ) exhibited peak expression specifically in B cells, while rhag ( 48 ) and transcripts of prdx2 ( 49 ) and slc4a1a ( 50 ) were found only in erythrocytes (Figure 1E).…”

“…These cells are self-renewing, nonmigratory and immunoregulatory (23). Conversely, the transcriptional profiles of zebrafish inflammatory macrophages resemble those of CD68 + MARCOcells in humans, which express high levels of cd74a (45), cd74b (45), cxcr4b (45) and ccr9a (45) and are inflammatory (23). In addition, it is worth noting that the Marco gene is a homologous gene of human MARCO.…”

“…The immune cell types identified included lymphocytes (expressing zap70 (32), il7r (33) and ifng1 (34)), neutrophils/monocytes (expressing mmp13a (35), mmp9 (36), lyz (37) and lect2l (38)), and eosinosphils (expressing viml (39), hp (39), cd81a (39) and gata2a (39)). Marco (40), cxcl8a (41) and csf1ra (42) were highly expressed in noninflammatory macrophages, while grn1 (43), mpeg1.1 (44) and cxcr4b (45) were predominantly expressed in inflammatory macrophages.…”

Bladder Oxidative Stress and HMGB1 Release Contribute to PAR4-Mediated Bladder Pain in Mice

“…We evaluated micturition parameters in awake mice with the VSOP method as reported (Ye et al, 2021) in order to exclude the possibility that the treatments may affect bladder function. No statistically significant differences were observed in micturition volume (F = 0.43, ns) or frequency (F = 1.947, ns) between the control group (PBS pre-treatment and scrambled peptide) and any of the other groups (Table 2).…”

“…We have studied the mechanisms of bladder pain using a rodent model that results in minimal damage to the organ while still producing bladder pain (Kouzoukas et al, 2015(Kouzoukas et al, , 2016Ma et al, 2018Ma et al, , 2019bYe et al, 2021). In this model, activation of urothelial protease activated receptors leads to release of urothelial MIF.…”