Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.

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Background-Sustained cardiac pressure overload-induced hypertrophy and pathological remodeling frequently leads to heart failure. Casein kinase-2 interacting protein-1 (CKIP-1) has been identified to be an important regulator of cell proliferation, differentiation, and apoptosis. However, the physiological role of CKIP-1 in the heart is unknown. Methods and Results-The results of echocardiography and histology demonstrate that CKIP-1-deficient mice exhibit spontaneous cardiac hypertrophy with aging and hypersensitivity to pressure overload-induced pathological cardiac hypertrophy, as well. Transgenic mice with cardiac-specific overexpression of CKIP-1 showed resistance to cardiac hypertrophy in response to pressure overload. The results of GST pull-down and coimmunoprecipitation assays showed the interaction between CKIP-1 and histone deacetylase 4 (HDAC4), through which they synergistically inhibited transcriptional activity of myocyte-specific enhancer factor 2C. By directly interacting with the catalytic subunit of phosphatase 2A, CKIP-1 overexpression enhanced the binding of catalytic subunit of phosphatase-2A to HDAC4 and promoted HDAC4 dephosphorylation. Conclusions-CKIP-1 was found to be an inhibitor of cardiac hypertrophy by upregulating the dephosphorylation of HDAC4 through the recruitment of protein phosphatase 2A. These results demonstrated a unique function of CKIP-1, by which it suppresses cardiac hypertrophy through its capacity to regulate HDAC4 dephosphorylation and fetal cardiac genes expression. (Circulation. 2012;126:3028-3040.)Key Words: hypertrophy Ⅲ molecular biology Ⅲ cardiomyopathy Ⅲ heart failure D espite recent treatment advances, heart failure continues to impose a substantial healthcare burden. One of the major risk factors for developing heart failure is preexisting cardiac hypertrophy resulting from pathological stimuli, such as long-standing hypertension or myocardial infarction. 1,2 Among the intracellular signaling pathways involved in the regulation of cardiac hypertrophy, class II histone deacetylases (HDACs) act as signal-responsive repressors by inhibiting the activity of myocyte-specific enhancer factor 2C (MEF2C) in the nucleus. [3][4][5] Dynamic nucleocytoplasmic shuttling has been proposed as one of the most fundamental mechanisms regulating the function of class II HDACs. 4,6,7 Phosphorylation of class II HDACs at specific serine residues after hypertrophic stimulation induces its interaction with 14-3-3, through which the class II HDACs are exported to the cytosol, where they can no longer suppress target transcription factors. 4,8 -10 In the heart, nuclear export of class II HDACs directly elicits activation of myocyte enhancer factor-2 (MEF2), which is a master positive regulator of cardiac hypertrophy. Serine/threonine protein phosphatase 2A (PP2A) could interact with and dephosphorylate HDAC4, thus reinforcing its nuclear accumulation. 11,12 However, little is known about the regulation of HDAC4 dephosphorylation in response to extracellular stimuli leading to car...