Microglial reactivity in brainstem chemosensory nuclei in response to hypercapnia.

Microglia, the resident immune cells of the CNS, surveil, detect, and respond to various extracellular signals. Depending on the nature of these signals, an integrative microglial response can be triggered, resulting in a phenotypic transformation. Here, we evaluate whether hypercapnia modifies microglia phenotype in brainstem respiratory-related nuclei. Adult C57BL/6 inbred mice were exposed to 10% CO2 enriched air (hypercapnia), or pure air (control), for 10 or 30 min and immediately processed for immunohistochemistry to detect the ubiquitous microglia marker, ionized calcium binding adaptor molecule 1 (Iba1). Hypercapnia for thirty, but not 10 min reduced the Iba1 labeling percent coverage in the ventral respiratory column (VRC), raphe nucleus (RN), and nucleus tractus solitarius (NTS) and the number of primary branches in VRC. The morphological changes persisted, at least, for 60 min breathing air after the hypercapnic challenge. No significant changes were observed in Iba1+ cells in the spinal trigeminal nucleus (Sp5) and the hippocampus. In CF-1 outbred mice, 10% CO2 followed by 60 min of breathing air, resulted in the reduction of Iba1 labeling percent coverage and the number and length of primary branches in VRC, RN, and NTS. No morphological change was observed in Iba1+ cells in Sp5 and hippocampus. Double immunofluorescence revealed that prolonged hypercapnia increased the expression of CD86, an inflammatory marker for reactive state microglia, in Iba1+ cells in VRC, RN, and NTS, but not in Sp5 and hippocampus in CF-1 mice. By contrast, the expression of CD206, a marker of regulatory state microglia, persisted unmodified. In brainstem, but not in hippocampal microglia cultures, hypercapnia increased the level of IL1ß, but not that of TGFß measured by ELISA. Our results show that microglia from respiratory-related chemosensory nuclei, are reactive to prolonged hypercapnia acquiring an inflammatory-like phenotype.

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice.

Current treatments for systemic autoimmune diseases partially improve the health of patients displaying low pharmacological efficacy and systemic immunosuppression. Here, the therapeutic potential of transferring tolerogenic dendritic cells (tolDCs) generated with heme-oxygenase inductor cobalt (III) protoporphyrin IX (CoPP), dexamethasone and rosiglitazone for the treatment of systemic autoimmunity was evaluated in two murine models of systemic lupus erythematosus (SLE), MRL-Faslpr and NZM2410 mice. Dendritic cells treated ex vivo with these drugs showed a stable tolerogenic profile after lipopolysaccharide stimulation. Regular doses of tolDCs were administered to anti-nuclear antibody-positive mice throughout 60-70 days, and the clinical score was evaluated. Long-term treatment with these tolDCs was well tolerated and effective to improve the clinical score on MRL-Faslpr lupus-prone mice. Additionally, decreased levels of anti-nuclear antibodies in NZM2410 mice were observed. Although tolDC treatment increased regulatory T cells, no significant reduction of renal damage or glomerulonephritis could be found. In conclusion, these results suggest that the transfer of histone-loaded tolDCs could improve only some SLE symptoms and reduced anti-nuclear antibodies. This is the first study to evaluate antigen-specific tolDC administration to treat SLE. Our report strengthens the clinical relevance of tolDC generation with CoPP, dexamethasone and rosiglitazone and the use of these modified cells as a therapy for systemic autoimmunity.

Carotid Body Type-I Cells Under Chronic Sustained Hypoxia: Focus on Metabolism and Membrane Excitability.

Chronic sustained hypoxia (CSH) evokes ventilatory acclimatization characterized by a progressive hyperventilation due to a potentiation of the carotid body (CB) chemosensory response to hypoxia. The transduction of the hypoxic stimulus in the CB begins with the inhibition of K+ currents in the chemosensory (type-I) cells, which in turn leads to membrane depolarization, Ca2+ entry and the subsequent release of one- or more-excitatory neurotransmitters. Several studies have shown that CSH modifies both the level of transmitters and chemoreceptor cell metabolism within the CB. Most of these studies have been focused on the role played by such putative transmitters and modulators of CB chemoreception, but less is known about the effect of CSH on metabolism and membrane excitability of type-I cells. In this mini-review, we will examine the effects of CSH on the ion channels activity and excitability of type-I cell, with a particular focus on the effects of CSH on the TASK-like background K+ channel. We propose that changes on TASK-like channel activity induced by CSH may contribute to explain the potentiation of CB chemosensory activity.