Abstract
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.
Highlights
The innate immune system is the first line of host defense that responds to pathogens and gives rise to pain responses (Chavan et al, 2018; Chiu, 2018; Janeway and Medzhitov, 2002; Pinho-Ribeiro et al, 2017)
To determine the significance of TLR2 in complete Freund’s adjuvant (CFA)-induced pain states, we examined the effects of CFA in TLR2-null mice
There was an increase in paw withdrawal latencies following depletion of TLR2 (Figure 1J), suggesting that TLR2 is an important mediator of CFA-induced pain responses in both sexes
Summary
The innate immune system is the first line of host defense that responds to pathogens and gives rise to pain responses (Chavan et al, 2018; Chiu, 2018; Janeway and Medzhitov, 2002; Pinho-Ribeiro et al, 2017). Innate immunity is activated by pathogen- or damage-associated molecular patterns through pattern recognition receptors, including Toll-like receptors (TLRs) and nod-like receptors (NLRs) (Brubaker et al, 2015; Lotze et al, 2007; Mogensen, 2009). It has been reported that TLR4 is upregulated during inflammation and following nerve injury (Raghavendra et al, 2003; Raghavendra et al, 2004) and contributes to neuropathic pain (Tanga et al, 2005). More TLRs have subsequently been reported to contribute to pain processing. How TLR activation gives rise to pain during innate immune activation is largely unknown
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