Neural crest mural cells of forebrain meninges harbor innate immune functions during early brain development and exhibit different responses to septic and toxic insults
In vertebrates, the cephalic neural crest (CNC), an embryonic multipotent cell population, gives rise to meningeal derivatives, covering and protecting the developing forebrain. In postnatal life, the meninges exert a prime role in developing and maintaining the central nervous systems homeostasis and help modulate the immune capacities of resident cells and the blood-brain barrier. However, their role in the embryo remains elusive before the formation of brain barriers. Here, we explore whether meningeal CNC-mural cells participate in immunosurveillance during the early stages of embryogenesis. Using primary cultures of E8 chicken forebrain meningeal mural cells, immuno-phenotyping, and flow cytometry analyses, we demonstrated the expression of specific receptors, including TLRs and MHC class II molecules typically expressed in myeloid cells. Our experiments showed that when challenged by bacterial particles, CNC mural cells also have phagocytic capacities. Transcriptomic analysis revealed activation of inflammatory pathways leading to increased expression of myeloid surface markers and the production of cytokines and interleukins in the presence of bacterial particles. Our in vitro assays also show the capacities of mural cells to present and transfer antigen particles and recruit cooperant cells, both locally and at a distance. Moreover, we revealed that pericytes could deploy DNA traps like neutrophils to stop pathogens. We show that mural cells use extracellular DNA shedding against pathogenic conditions and communicate with each other to mobilize cell cooperation. Transcriptomic analyses revealed that exposure to bacterial particles leads to severe impairment of morphogenetic and neuro-developmental pathways and shed light on the possible detrimental effect of bacterial infection on brain development and maturation of cognitive functions. To reinforce the possible link between neurodevelopmental defects and immune activation, we challenged the immune capacities of CNC pericytes after exposure to toxic medication. We used Valproate (VPA), an antiepileptic drug associated with developmental disorders in newborns when administered during pregnancy. We show that VPA injection into chicken embryos triggered exacerbated myeloid traits and DNA trap releases in CNC pericytes. Our studies show that CNC mural cells are professional innate immune cells capable of pathogen recognition and antigen presentation. This notion breaks the prevailing concept that only mesodermal lineage can participate in the innate immune defense. It opens new avenues for elaborating brain-specific immunity before birth, which may have important biomedical implications for neurodevelopmental disorders.