Abstract
BackgroundC-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection.MethodsThe inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains.ResultsGlobal expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T-cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury.ConclusionsIn summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival.
Highlights
Both innate and adaptive immune responses, involving local as well as blood-derived immune cells, have been shown to exert both protective and detrimental effects after traumatic nerve injuries, but there is still limited knowledge on how this regulation is executed.Probably the most studied immune cells, with regard to traumatically induced immune responses, are the microglia [1], which are a versatile and heterogeneous cell population
Since early reactions following injury likely affect downstream events, such as nerve cell death, we set up an F2 (DAxPVG) intercross and performed global transcriptional profiling of injured spinal cords combined with whole-genome linkage analysis to define Expression quantitative trait loci (eQTL)
We here demonstrate that a genetic variation occurring between inbred DA and PVG rats in the antigenpresenting lectin-like receptor gene complex (Aplec) cluster, which encodes six characterized C-type lectin genes, significantly affects survival of axotomized motor neurons and T-cell infiltration after nerve root injury
Summary
Both innate and adaptive immune responses, involving local as well as blood-derived immune cells, have been shown to exert both protective and detrimental effects after traumatic nerve injuries, but there is still limited knowledge on how this regulation is executed.Probably the most studied immune cells, with regard to traumatically induced immune responses, are the microglia [1], which are a versatile and heterogeneous cell population. Both innate and adaptive immune responses, involving local as well as blood-derived immune cells, have been shown to exert both protective and detrimental effects after traumatic nerve injuries, but there is still limited knowledge on how this regulation is executed. Like neutrophils [3], monocytes and macrophages [4], infiltrate the CNS after acute injuries. Regarding the role of cells from the adaptive immune system following traumatic CNS injuries, both T and B cells have been shown to confer both protective and deleterious effects [8,9,10]. C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection
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