CNS‐infiltrating CD4⁺ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

Abstract

We previously reported leukocytic infiltration into the lumbar spinal cord in a rodent spinal nerve L5 transection (L5Tx) neuropathic pain model. Here, we further investigated the role of infiltrating T lymphocytes in the etiology of persistent pain following L5Tx. T lymphocyte-deficient nude mice showed no evident mechanical hypersensitivity after day 3 of L5Tx compared to wild-type BALB/c mice. Through FACS analysis, we determined that significant leukocytic infiltration (CD45 hi ) into the lumbar spinal cord peaked at day 7 post L5Tx. These infiltrating leukocytes contained predominantly CD4 + but not CD8 + T lymphocytes. B lymphocytes, natural killer cells and macrophages were not detected at day 7 post L5Tx. No differences in the activation of peripheral CD4 + T lymphocytes were detected in either the spleen or lumbar lymph nodes between L5Tx and sham surgery groups. Further, CD4 KO mice displayed significantly decreased mechanical hypersensitivity after day 7 of L5Tx, and adoptive transfer of CD4 + leukocytes reversed this effect. Decreased immunoreactivity of glial fibrillary acidic protein observed in CD4 KO mice post L5Tx indicated possible T lymphocyte-glial interactions. These results strongly support a contributing role of spinal cord-infiltrating CD4 + T lymphocytes versus peripheral CD4 + T lymphocytes in the maintenance of nerve injury-induced neuropathic pain.

Peripheral Nerve Injury Alters Blood-Spinal Cord Barrier Functional and Molecular Integrity through a Selective Inflammatory Pathway

“…PNI-induced recruitment of GFP ϩ cells was also significantly reduced in the spinal cord parenchyma of chimeric mice treated with TGF-␤1. The ability of circulating immune cells to populate the CNS is further supported by T-lymphocyte infiltration observed in rats having spared nerve injury (Costigan et al, 2009) or partial sciatic nerve injury (current study) and in mice having spinal nerve transection (Cao and DeLeo, 2008). The cross talk between the immune and nervous systems through impaired BBB/BSCB may have significant impact on long-term molecular and cellular changes in pain pathways and persistent pain behavior.…”

“…Within the spinal cords, remote injury induces substantial changes in microglia and astrocytes, which are important players in the central inflammatory response (Zhang and De Koninck, 2009). In addition, peripheral nerve injury (PNI) evoked trafficking of immune cells from circulation into the spinal cord parenchyma (Zhang et al, 2007;Cao and DeLeo, 2008;Costigan et al, 2009). These neuroimmune interactions participate in the pathogenesis of chronic pain states (McMahon and Malcangio, 2009;White et al, 2009).…”

ATP receptors gate microglia signaling in neuropathic pain

“…Indeed, afferent barrage after the nerve injury is thought to trigger neuropathic pain by activating p38 in spinal microglia (Wen et al, 2007). One such consequence of peripheral nerve injury is the entry of blood bourn immune cells into the central nervous system (Sweitzer et al, 2002a), specifically, these cells include monocytes , and T-lymphocytes (Cao and DeLeo, 2008;Costigan et al, 2009a). Transit of these cells is likely aided by increased permeability of the blood brain barrier and the blood spinal cord barrier Echeverry et al, 2011;Gordh and Sharma, 2006).…”

Glia in pathological pain: A role for fractalkine

“…Although fractlakine is responsible for the recruitment of natural killer cells during neurodegenerative conditions in animal models for MS or ALS, as well as mediates pain in animal models for neuropathic pain, other innate immune cells (leukocytes) and lymphocytes (T cells) are characterized to migrate into pain relevant areas of the spinal cord during neuropathic pain conditions (Cao andDeLeo, 2008, Sweitzer et al, 2002). The chemoattractant(s) responsible for spinal cord lymphocyte and leukocyte trafficking specifically during neuropathic pain conditions remains unknown.…”