The role of TLR2 in nerve injury-induced neuropathic pain is essentially mediated through macrophages in peripheral inflammatory response.

Activation of macrophages/microglia via toll-like receptors (TLRs) plays an important role in inflammation and host defense against pathogens. Pathogen-associated molecular patterns bind TLRs, thereby triggering NF-κB signaling and production of proinflammatory cytokines. Recent data suggest that nonpathogenic molecules resulting from trauma can also trigger inflammation via TLRs. We sought to determine whether peripheral nerve injury could induce the expression of TLR2 on the site of injury-damaged nerves and/or in the central nervous system and to investigate whether TLR2 is necessary for the development of nerve injury-induced neuropathic pain. We observed a significant increase in TLR2, IκB-α, and TNF-α mRNAs in damaged nerves. Increased inflammation-related molecules were found essentially on ED1(+) macrophages. Expression of both IκB-α and TNF-α in peripheral injured nerves was reduced in TLR2 deficient mice where the recruitment of ED1(+) cells is significantly impaired. Although after peripheral nerve injury, spinal microglia became highly activated showing an increase in Iba-1 immunoreactivity and an enlargement of their cell bodies, neither TLR2 mRNA nor IκB-α mRNA was detected in activated microglia. Nerve injury-evoked spinal microglial activation was not significantly altered in TLR2 KO mice. Paw withdrawal threshold and latency in response to mechanical and heat stimuli, respectively, decreased shortly after nerve lesion in wild type mice. In TLR2 KO mice, nerve injury-induced thermal hyperalgesia was completely abolished contrary to that seen in wild-type mice, whereas mechanical allodynia was partially reduced. We suggest that TLR2 is necessary for the development of neuropathic pain and its contribution is more important in thermal hypersensitivity than that of mechanical allodynia.