Selectively reducing cytokine/chemokine expressing macrophages in injured nerves impairs the development of neuropathic pain.

It has been well documented that Wallerian degeneration following nerve injury is associated with inflammatory reaction. Such local inflammation contributes to the development of chronic neuropathic pain. Macrophages are one of the major players in the process of either or both degeneration/regeneration and hypersensitivity. To elucidate whether cellular and molecular changes involved in Wallerian degeneration are simultaneously involved in the induction and maintenance of neuropathic pain, and to identify which subpopulation of macrophages can be responsible for the chronic pain following nerve injury, we investigated the peripheral effects of an anti-inflammatory cytokine TGF-β1 in neuropathic pain. Rat sciatic nerves were partially ligated. Macrophages accumulated in injured sciatic nerves displayed heterogeneity with two distinctive functional phenotypes. While MAC1(+) macrophages were able to express IL-6 and MIP-1α, ED1(+) macrophages were always devoid of signals of inflammatory mediators. Intraneural injection of TGF-β1 resulted in delayed and attenuated neuropathic pain behaviour. In parallel, we observed that exposure of the nerve to TGF-β1 dramatically reduced the number of MAC1(+) macrophages. Consequently, the expression of IL-6 and MIP-1α decreased in the injured nerve. Very interestingly, local TGF-β1 treatment had no effect on the population of ED1(+) phagocytic macrophages. In addition to its effect on selective subsets of macrophages, TGF-β1 also reduced T-lymphocyte infiltration. Our results revealed the critical roles of cytokine/chemokine secreting MAC1(+) macrophages in the development of neuropathic pain, and highlighted the needs and benefits of targeting specific populations of macrophages in alleviating neuropathic pain without delaying nerve regeneration.