Hyperactivity of Innate Immunity Triggers Pain via TLR2-IL-33-Mediated Neuroimmune Crosstalk

• Published in: Cell reports (Cambridge) 2020-10, Vol.33 (1), p.108233-108233, Article 108233
• Main Authors: Huang, Junting, Gandini, Maria A., Chen, Lina, M’Dahoma, Said, Stemkowski, Patrick L., Chung, Hyunjae, Muruve, Daniel A., Zamponi, Gerald W.
• Format: Article
• Language: English
• Subjects: IL-33/ST2; innate immunity; NLRP3; pain; sensory neurons; TLR2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108233

The innate immune system responds to infections that give rise to pain. How the innate immune system interacts with the sensory nervous system and contributes to pain is poorly understood. Here we report that hyperactivity of innate immunity primes and initiates pain states via the TLR2-interleukin-33 (IL-33) axis. Toll-like receptors (TLRs) are upregulated in the complete Freund’s adjuvant (CFA) pain model, and knockout of TLR2 abolishes CFA-induced pain. Selective activation of TLR2/6 triggers acute pain via upregulation of IL-33 in the hindpaw, dorsal root ganglia (DRG), and spinal cord in an NLRP3-dependent manner. The IL-33 increase further initiates priming of nociceptive neurons and pain states. Finally, blocking IL-33 receptors at the spinal level mediates analgesia during acute and chronic inflammatory pain, underscoring an important function of IL-33 in pain signaling. Collectively, our data reveal a critical role of the TLR2-IL-33 axis in innate immune activation for pain initiation and maintenance. [Display omitted] •Toll-like receptors are upregulated during CFA-induced inflammatory pain•TLR2/6 receptor activation triggers acute pain via NLRP3-dependent upregulation of IL-33•IL-33 primes pain responses via neuroimmune crosstalk•Blocking IL-33 receptors mediates analgesia during inflammatory pain states Huang et al. describe a cellular mechanism that mediates pain responses resulting from bacterial pathogen-associated infection. They show that activation of innate immunity triggers pain by activation of TLR2 receptors and production of IL-33. Blocking IL-33 receptors at the spinal level mediates analgesia in mouse models of inflammatory pain.