MIS416 enhances recovery from traumatic spinal cord injury (SCI) in mice by regulating the innate immune response

Spinal cord injury (SCI) has devastating consequences, few efficacious treatment options with improving functional outcome a major therapeutic aim. SCI resolution is modulated by neuroinflammation, which is augmented by the infiltration of immune cells from the circulation that can be beneficial or detrimental and therefore has been targeted therapeutically in SCI. Here we sought to investigate the therapeutic application of MIS416, a novel immunomodulatory drug in clinical development that specifically targets myeloid cell responses, in enhancing recovery following traumatic SCI in mice. Severe contusive SCI (70 kilo dyne) was induced in WT mice and locomotor functional recovery was assessed on day 1,7,14, 21 and 28 post SCI using the Basso Mouse Scale (BMS). MIS416 (6-12mg/kg) was administered intravenously 24hr following SCI and weekly thereafter. Immune cells were isolated from peripheral blood and the whole spinal cord, phenotyped using flow cytometry, immunohistology, and correlated with BMS scores for functional recovery. MIS416 treated mice showed significantly augmented functional recovery compared to untreated mice. MIS416 treatment decreased the number of proinflammatory granulocytes/neutrophils in peripheral blood at 7 dpi that were negatively correlated with functional recovery. Additionally, MIS416 treatment was associated with increased numbers of CD115+ bone marrow derived monocytes in the peripheral blood of mice with SCI at 7 dpi with a bias towards a non-inflammatory phenotype. Further, the magnitude of this expansion positively correlated with functional recovery. Additionally, MIS416 decreased the ratio of microglia to peripherally derived leucocytes in the whole spinal cord at 28 dpi, indicating there was concomitant increased infiltration of peripheral blood leucocytes as a result of injury. MIS416 treatment was also associated with increased microglial activation at 28 dpi, a proportion of which were CD11c+ microglia, a potentially tissue protective phenotype. Together, these results highlight the beneficial role of MIS416 in SCI mediated by expanding non-inflammatory bone marrow derived monocytes and limiting inflammatory leucocyte available to be recruited to the injury site, in addition to modulating microglial function. In conclusion, MIS416 may be a novel therapeutic candidate for traumatic SCI.