Hyperactivity of Innate Immunity Triggers Pain via TLR2-IL-33-Mediated Neuroimmune Crosstalk
Junting Huang,
Maria A. Gandini,
Lina Chen,
Said M’Dahoma,
Patrick L. Stemkowski,
Hyunjae Chung,
Daniel A. Muruve,
Gerald W. Zamponi
Affiliations
Junting Huang
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Corresponding author
Maria A. Gandini
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Lina Chen
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Said M’Dahoma
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Patrick L. Stemkowski
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Hyunjae Chung
Department of Medicine, Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Daniel A. Muruve
Department of Medicine, Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Gerald W. Zamponi
Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; Corresponding author
Summary: 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.
