Macrophage prostaglandin E2 mediates inflammatory pain in peripheral tissues

AbstractCirculating immune cells, which are recruited to the site of injury/disease, secrete various inflammatory mediators that are critical to nociception and pain. The role of tissue-resident immune cells, however, remains poorly characterized. One of the first cells to be activated in peripheral tissues following injury are γδ T cells, which serve important roles in infection and disease. Using a transgenic mouse line lacking these cells, we sought to identify their contribution to inflammatory pain. Three distinct models of inflammatory pain were used: intraplantar injection of formalin and incisional wound (as models of acute inflammatory pain) and intraplantar injection of complete Freund’s adjuvant (as a model of chronic inflammatory pain). Our results show that absence of these cells does not alter baseline sensitivity, nor does it result in changes to mechanical or thermal hypersensitivity after tissue injury. These results were consistent in both male and female mice, suggesting that there are no sex differences in these outcomes. This comprehensive characterization suggests that γδ T cells do not contribute to basal sensitivity or the development and maintenance of inflammatory pain.

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IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2

British Journal of Pharmacology ◽

10.1111/bph.12110 ◽

2013 ◽

Vol 169 (1) ◽

pp. 90-101 ◽

Cited By ~ 56

Author(s):

AC Zarpelon ◽

TM Cunha ◽

JC Alves-Filho ◽

LG Pinto ◽

SH Ferreira ◽

...

Keyword(s):

Prostaglandin E2 ◽

Inflammatory Pain ◽

Endothelin 1

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Chemistry and biology of microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors as novel anti-inflammatory agents: recent developments and current status

RSC Advances ◽

10.1039/c5ra25186a ◽

2016 ◽

Vol 6 (34) ◽

pp. 28343-28369 ◽

Cited By ~ 9

Author(s):

Puneet Khurana ◽

Sanjay M. Jachak

Keyword(s):

Prostaglandin E2 ◽

Inflammatory Pain ◽

Current Status ◽

Recent Developments ◽

Anti Inflammatory

Prostaglandin (PG) E2, a key mediator of inflammatory pain and fever, is biosynthesized from PGH2 by mPGES-1.

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Investigational drugs targeting the prostaglandin E2 signaling pathway for the treatment of inflammatory pain

Expert Opinion on Investigational Drugs ◽

10.1080/13543784.2017.1260544 ◽

2016 ◽

Vol 26 (1) ◽

pp. 51-61 ◽

Cited By ~ 19

Author(s):

Sabine Grösch ◽

Ellen Niederberger ◽

Gerd Geisslinger

Keyword(s):

Prostaglandin E2 ◽

Signaling Pathway ◽

Inflammatory Pain ◽

Investigational Drugs

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Prostaglandin E2 Receptor EP4 Contributes to Inflammatory Pain Hypersensitivity

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.106.105569 ◽

2006 ◽

Vol 319 (3) ◽

pp. 1096-1103 ◽

Cited By ~ 154

Author(s):

Chung-Ren Lin ◽

Fumimasa Amaya ◽

Lee Barrett ◽

Haibin Wang ◽

Junji Takada ◽

...

Keyword(s):

Prostaglandin E2 ◽

Inflammatory Pain ◽

Pain Hypersensitivity ◽

Prostaglandin E2 Receptor

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Electroacupuncture Attenuates Inflammatory Pain by Activating AMPK/autophagy and Inhibiting iNOS and IL-1β in Inflamed Tissues

10.21203/rs.3.rs-968621/v1 ◽

2021 ◽

Author(s):

Hongchun Xiang ◽

Guowei Cai ◽

Liang Hu ◽

Yuye Lan ◽

Tao Weng ◽

...

Keyword(s):

Inflammatory Pain ◽

Thermal Hyperalgesia ◽

Adenosine Monophosphate ◽

Peripheral Tissues ◽

Analgesic Effects ◽

Substrate Protein ◽

Compound C ◽

Amp Activated Protein Kinase

Abstract BackgroundElectroacupuncture (EA) produces analgesic effects on inflammatory pain partially via activating adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in the spinal cord. However, it is unclear whether EA activates AMPK in peripheral tissues in inflammatory pain. This study was aimed at determining whether EA promotes autophagy by activating AMPK to inhibit the expression of inflammatory mediators IL-1β and iNOS in inflamed skin tissues. MethodsIn CFA-induced inflammatory pain in mice, mechanical allodynia and thermal hyperalgesia were tested 2 hours after EA treatment. The AMPK antagonist Compound C was injected intraperitoneally 30 minutes before EA treatment. The analgesic effects of AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) were determined and its effects on autophagy, IL-1β and iNOS expression were detected. Also, the effects of the autophagy inhibitor 3-methyladenine (3-MA) on EA analgesia and iNOS/IL-1β expression in inflamed skin tissues were examined. The phosphorylation of AMPK (Thr172) and total AMPK proteins, LC3BII/I, autophagy substrate protein p62, IL-1β and iNOS were detected using Western blotting. Co-labeling of macrophages (CD68) with IL-1β and iNOS was detected using immunofluorescence. In addition, after NR8383 macrophages were treated with CFA, the effects of AICAR and Compound C on autophagy were determined using stubRFP-sensGFP-LC3 Lentivirus..ResultsEA reduced CFA-induced inflammatory pain, activated AMPK and autophagy, and inhibited iNOS and IL-1β expression in inflamed skin tissues. AICAR also attenuated CFA-induced hyperalgesia, promoted autophagy and inhibited iNOS and IL-1β expression in vivo and in vitro. In addition, the AMPK inhibitor Compound C reversed the effect of EA on autophagy. Pretreatment with 3-MA, an inhibitor of autophagy, inhibited the effect of EA on inflammatory pain and expression of iNOS and IL-1β in inflamed skin tissues. ConclusionsEA treatment alleviated inflammatory pain by activation of AMPK, enhancing autophagy, and inhibiting iNOS and IL-1β expression in the inflamed skin tissues.

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Prostaglandin E2 is a key factor for CCR7 surface expression and migration of monocyte-derived dendritic cells

Blood ◽

10.1182/blood-2001-11-0017 ◽

2002 ◽

Vol 100 (4) ◽

pp. 1354-1361 ◽

Cited By ~ 350

Author(s):

Elke Scandella ◽

Ying Men ◽

Silke Gillessen ◽

Reinhold Förster ◽

Marcus Groettrup

Keyword(s):

Dendritic Cells ◽

Lymph Node ◽

T Cell ◽

Prostaglandin E2 ◽

Cyclic Adenosine Monophosphate ◽

Human Monocyte ◽

Adenosine Monophosphate ◽

Cd40 Ligand ◽

Soluble Cd40 Ligand ◽

Peripheral Tissues

Dendritic cells (DCs) are potent antigen-presenting cells that are able to initiate and modulate immune responses and are hence exploited as cellular vaccines for immunotherapy. Their capacity to migrate from peripheral tissues to the T-cell areas of draining lymph nodes is crucial for the priming of T lymphocytes. In this study, we investigated how the maturation of human monocyte-derived DCs (MoDCs) by several different stimuli under serum-free conditions affected their T-cell stimulatory function, cytokine secretion, and migratory behavior. Surprisingly, we found that for all maturation stimuli tested, the addition of prostaglandin E2 (PGE2) was required for effective migration of MoDCs toward the lymph node–derived chemokines CCL19 (EBI1 ligand chemokine/macrophage inflammatory protein–-3β) and CCL21 (secondary lymphoid tissue chemokine [SLC]/6Ckine). Costimulation with PGE2 enhanced the expression of the CCL19/CCL21 receptor CCR7 on the cell surface of MoDCs when they were matured with soluble CD40 ligand or proinflammatory cytokines, but did not affect CCR7 expression of polyI:C–stimulated MoDCs. The effects of PGE2 on MoDCs were mediated through increased cyclic adenosine monophosphate by 2 of the known PGE2 receptors, EP2 and EP4, which are expressed and down-regulated after PGE2 binding in these cells. In conclusion, our results suggest that signals provided by the proinflammatory mediator PGE2 are crucial for MoDCs to acquire potent T-helper cell stimulatory capacity and substantial chemotactic responsiveness to lymph node–derived chemokines. This is a new and important parameter for the preparation of MoDCs as cellular vaccines in tumor immunotherapy.

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