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The immunoaffinity isolation of neuron-derived extracellular vesicles (NDEVs) from blood by targeting the neuronal protein L1CAM has been widely adopted to provide peripheral biomarkers for brain disorders. However, compelling evidence for the presence of L1CAM on NDEVs at the single-EV level has been missing. Here, we demonstrate that L1CAM co-localizes with EV-characteristic and neuronal markers in plasma EVs, and quantify the enrichment achieved after L1CAM immunoprecipitation, validating the NDEV isolation methodology.

Studies in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) suggest that peripheral monocyte-derived cells (MDCs) are instrumental for disease initiation. MDCs, however, are plastic, and may exert various functions once in the central nervous system (CNS) for prolonged periods. Furthermore, the long-term effect of MDC depletion on continuing axon loss is not known. We show that long-lasting depletion of MDCs, after onset of EAE clinical deficits, is accompanied by decreased CNS infiltration by pathogenic T lymphocytes. Although this treatment does not reverse clinical disease, it prevents worsening of neurological deficits and long-term axonal loss.

Severe trauma such as burn injury is often associated with a systemic inflammatory syndrome characterized by a hyperactive innate immune response and suppressed adaptive immune function. Dendritic cells (DCs), which sense pathogens via their Toll-like receptors (TLRs), play a pivotal role in protecting the host against infections. The effect of burn injury on TLR-mediated DC function is a debated topic and the mechanism controlling the purported immunosuppressive response remains to be elucidated. Here we examined the effects of burn injury on splenic conventional DC (cDC) and plasmacytoid DC (pDC) responses to TLR9 activation. We demonstrate that, following burn trauma, splenic cDCs' cytokine production profile in response to TLR9 activation became anti-inflammatory dominant, with high production of IL-10 (>50% increase) and low production of IL-6, TNF-α and IL-12p70 (∼25-60% reduction). CD4+ T cells activated by these cDCs were defective in producing Th1 and Th17 cytokines. Furthermore, burn injury had a more accentuated effect on pDCs than on cDCs. Following TLR9 activation, pDCs displayed an immature phenotype with an impaired ability to secrete pro-inflammatory cytokines (IFN-α, IL-6 and TNF-α) and to activate T cell proliferation. Moreover, cDCs and pDCs from burn-injured mice had low transcript levels of TLR9 and several key molecules of the TLR signaling pathway. Although hyperactive innate immune response has been associated with severe injury, our data show to the contrary that DCs, as a key player in the innate immune system, had impaired TLR9 reactivity, an anti-inflammatory phenotype, and a dysfunctional T cell-priming ability. We conclude that burn injury induced impairments in DC immunobiology resulting in suppression of adaptive immune response. Targeted DC immunotherapies to promote their ability in triggering T cell immunity may represent a strategy to improve immune defenses against infection following burn injury.

Impaired healing after severe burns remains a reason for prolonged hospitalization, opportunistic infections, and debilitating scarring. Interferon-gamma (IFN-γ) is an important immune regulator that has been shown to inhibit collagen synthesis by fibroblasts, resulting in delayed healing in incision wounds. To determine whether IFN-γ plays similar roles in the healing process after severe burn, we induced scald injury in mice deficient or sufficient in IFN-γ and examined local responses. In the absence of IFN-γ, scalded areas healed faster. This was associated with attenuated local inflammatory responses, enhanced reepithelialization, increased proliferation of keratinocytes in reepithelialized leading edges, and up-regulation of growth factors in burned skin areas. Furthermore, angiogenesis and myofibroblast formation commenced and terminated earlier in IFN-γ(-/-) mice compared with wild type (WT) controls. Our observations demonstrate that inhibition of IFN-γ results in accelerated healing after burn injury by dampening excessive inflammation and facilitating reepithelialization, collagen deposition, and wound contraction.

Impaired healing after severe burns remains a reason for prolonged hospitalization, opportunistic infections, and debilitating scarring. Interferon-gamma (IFN-γ) is an important immune regulator that has been shown to inhibit collagen synthesis by fibroblasts, resulting in delayed healing in incision wounds. To determine whether IFN-γ plays similar roles in the healing process after severe burn, we induced scald injury in mice deficient or sufficient in IFN-γ and examined local responses. In the absence of IFN-γ, scalded areas healed faster. This was associated with attenuated local inflammatory responses, enhanced reepithelialization, increased proliferation of keratinocytes in reepithelialized leading edges, and up-regulation of growth factors in burned skin areas. Furthermore, angiogenesis and myofibroblast formation commenced and terminated earlier in IFN-γ(-/-) mice compared with wild type (WT) controls. Our observations demonstrate that inhibition of IFN-γ results in accelerated healing after burn injury by dampening excessive inflammation and facilitating reepithelialization, collagen deposition, and wound contraction.