IL-37, a member of the IL-1 family, broadly reduces innate inflammation as well as acquired immunity. Whether the antiinflammatory properties of IL-37 extend to the central nervous system remains unknown, however. In the present study, we subjected mice transgenic for human IL-37 (hIL-37tg) and wild-type (WT) mice to spinal cord contusion injury and then treated them with recombinant human . In the hIL-37tg mice, the expression of IL-37 was barely detectable in the uninjured cords, but was strongly induced at 24 h and 72 h after the spinal cord injury (SCI). Compared with WT mice, hIL-37tg mice exhibited increased myelin and neuronal sparing and protection against locomotor deficits, including 2.5-fold greater speed in a forced treadmill challenge. Reduced levels of cytokines (e.g., an 80% reduction in IL-6) were observed in the injured cords of hIL-37tg mice, along with lower numbers of blood-borne neutrophils, macrophages, and activated microglia. We treated WT mice with a single intraspinal injection of either full-length or processed rIL-37 after the injury and found that the IL-37-treated mice had significantly enhanced locomotor skills in an open field using the Basso Mouse Scale, as well as supported faster speed on a mechanical treadmill. Treatment with both forms of rIL-37 led to similar beneficial effects on locomotor recovery after SCI. This study presents novel data indicating that IL-37 suppresses inflammation in a clinically relevant model of SCI, and suggests that rIL-37 may have therapeutic potential for the treatment of acute SCI.he inflammatory response plays an essential role in tissue protection after injury or invasion by microorganisms (1, 2). Regardless of the tissue, unless regulated, inflammation can become chronic and result in tissue damage and loss of function (1, 2). This is particularly the case in spinal cord injury (SCI). After spinal cord contusion or compression injury, there is a rapid initiation of inflammation in rodents and in humans (2). This response is orchestrated by endogenous microglial cells and by circulating leukocytes, especially monocytes and neutrophils, which invade the lesion site during the first hours and days after injury (2-4). Although these cells are required for the clearance of cellular and myelin debris, they also release cytokines and cytotoxic factors, which are harmful to neurons, glia, axons, and myelin, resulting in secondary damage to adjacent regions of the spinal cord that had been previously unaffected by the insult (2, 5, 6). Indeed, it is currently well accepted that inflammation is a major contributor to secondary cell death after SCI. The damaging effects of inflammation are more pronounced in the central nervous system (CNS) than in other tissues, because of the limited capacity for axon regeneration and replenishment of damaged neurons and glial cells, which leads to irreversible functional disabilities (7,8). Therefore, targeting inflammation is a valuable approach to promoting neuroprotection and limiting functional deficits in SCI.Cyt...
