43 Activation of CCL2/CCR2 Signaling Axis Is Responsible for Spinal Cord Inflammation and Loss of Muscle Mass in Mice After Burn Injury

Abstract Introduction Burn-induced systemic inflammation (BISI) can induce inflammatory responses in peripheral nervous system and also cause neuroinflammation in the central nervous system, leading to morbidity and mortality. The mechanisms of neuromotor impairment involving CCL2/CCR2 signaling axis are largely unknown. We hypothesized that BISI causes neuroinflammation in the spinal cord, and this inflammatory response can lead to motor neuronal damage, disintegration of nerve termini and eventually muscle wasting. Methods Cytokines/chemokines were estimated by Cytokine Antibody Array. Nerve termini and muscle fibers in abdominal muscle, and motor neuronal apoptosis in the spinal cord were analyzed by fluorescent microscopy and immunochemical analyses. Loss of muscle mass was assessed by wet weight of the muscles compared with control in mice after BISI. Results Our data showed that CCL2 was significantly increased in the serum (>2.4 fold) at day 1 and 3 after BISI in vivo. Iin the extracellular medium (>2.0 fold) of organotypic spinal cord explant after exposure to exogenous histones ex vivo at day1. Neuroinflammation in the spinal cord after BISI caused motor neuronal apoptosis, nerve termini disintegration, and loss of muscle mass of soleus (63.4 + 5.1%), tibialis (72.3 + 2.7%) and gastrocnemius (70.2 + 1.1%) compared to sham burn injured wild-type (WT) or YFP-neurons expressing transgenic mice. In contrast, GTS-21 reduced neuroinflammation and significantly prevented loss of muscle mass of soleus (86.8 + 0.2%), tibialis (85.4 + 4.5%) and gastrocnemius (89.0 + 4.0%). Depletion of macrophages by PBS-liposomes in burned mice showed transmigration of CCR2-containing monocytes-derived macrophages (CCR2-MDMΦ) in the ventral horn of the spinal cord, and led to the loss of all three muscles (soleus, 62.4 + 2.6%; tibialis, 86.3 + 3.5; gastrocnemius, 81.4 + 1.7%). Nevertheless, depletion of macrophages by Clophosomes in burned mice inhibited the transmigration of CCR2-MDMΦ, and protected muscle mass (soleus, 96.6 + 3.9%; tibialis, 101 + 3.9%; gastrocnemius, 98.3 + 1.2%) significantly. Subsequently, we demonstrated that the knocking out of CCR2 gene in mice protected motor neuronal apoptosis and inhibited loss of muscle mass of soleus, tibialis and gastrocnemius from 63.4 + 5.1%, 72.3 + 2.7% and 70.2 + 1.1% in WT mice to 82.1 + 4.7%, 85.4 + 4.5% and 95.8 + 3.2% in CCR2KO mice, respectively, after BISI. Conclusions Collectively, these results suggest activated macrophages creep to the spinal cord through CCL2/CCR2 signaling axis after BISI to cause neuroinflammation, leading to motor neuronal damage, nerve disintegration and muscle wasting. Applicability of Research to Practice These findings will be useful to understand the pathology occurring in burned patients and to develop the therapeutics measures to protect them from BISI.

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