Role of leukotriene B4 (LTB4)-LTB4 receptor 1 signaling in post-incisional nociceptive sensitization and local inflammation in mice

PLoS One. 2022 Oct 20;17(10):e0276135. doi: 10.1371/journal.pone.0276135. eCollection 2022.

Abstract

Leukotriene B4 (LTB4) is a potent lipid mediator involved in the recruitment and activation of neutrophils, which is an important feature of tissue injury and inflammation. The biological effects of LTB4 are primarily mediated through the high-affinity LTB4 receptor, BLT1. Postoperative incisional pain is characterized by persistent acute pain at the site of tissue injury and is associated with local inflammation. Here, we compared the role of LTB4-BLT1 signaling in postoperative incisional pain between BLT1-knockout (BLT1KO) and wild-type (BLT1WT) mice. A planter incision model was developed, and mechanical pain hypersensitivity was determined using the von Frey test before and after incision. Local infiltration of neutrophils and inflammatory monocytes was quantified by flow cytometry. Inflammatory cytokine levels in the incised tissue were also determined. Mechanical pain hypersensitivity was significantly reduced in BLT1KO mice compared to BLT1WT mice at 2, 3, and 4 days after incision. LTB4 levels in the tissue at the incision site peaked 3 hours after the incision. Infiltrated neutrophils peaked 1 day after the incision in both BLT1KO and BLT1WT mice. The accumulation of inflammatory monocytes increased 1-3 days after the incision and was significantly more reduced in BLT1KO mice than in BLT1WT mice. In BLT1KO mice, Interleukin-1β and Tumor Necrosis Factor-α levels 1 day after the incision were significantly lower than those of BLT1WT mice. Our data suggest that LTB4 is produced and activates its receptor BLT1 in the very early phase of tissue injury, and that LTB4-BLT1 signaling exacerbates pain responses by promoting local infiltration of inflammatory monocytes and cytokine production. Thus, LTB4-BLT1 signaling is a potential target for therapeutic intervention of acute and persistent pain induced by tissue injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines
  • Hypersensitivity*
  • Inflammation
  • Interleukin-1beta
  • Leukotriene B4
  • Mice
  • Mice, Knockout
  • Nociception
  • Pain
  • Receptors, Leukotriene B4* / genetics
  • Tumor Necrosis Factor-alpha

Substances

  • Receptors, Leukotriene B4
  • Leukotriene B4
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Cytokines

Grants and funding

This study was supported by Grants in Aid for Scientific Research, Japan Society for Promotion of Science (JSPS) in the form of grants awarded to NI (20K09190) and TY (18H02627 and 21H04798). This study was also supported by AMED in the form of a grant awarded to TY (22wm0425008s0201). The funders had no role in this study design, data collection and analysis, decision to publish, or preparation of the manuscript.