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

PLoS One. 2021 Aug 23;16(8):e0255975. doi: 10.1371/journal.pone.0255975. eCollection 2021.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Animals
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Female
  • HMGB1 Protein / genetics
  • HMGB1 Protein / metabolism*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / metabolism*
  • Humans
  • Hyperalgesia / etiology
  • Hyperalgesia / metabolism
  • Hyperalgesia / pathology*
  • Macrophage Migration-Inhibitory Factors / genetics
  • Macrophage Migration-Inhibitory Factors / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Thrombin / genetics
  • Receptors, Thrombin / metabolism*
  • Urinary Bladder / metabolism
  • Urinary Bladder / pathology*
  • Young Adult

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • CXCR4 protein, mouse
  • HMGB1 Protein
  • Histocompatibility Antigens Class II
  • Macrophage Migration-Inhibitory Factors
  • Receptors, CXCR4
  • Receptors, Immunologic
  • Receptors, Thrombin
  • invariant chain
  • macrophage migration inhibitory factor receptor
  • protease-activated receptor 4