Chemokine receptor CCR7 on CD4+ T cells plays a crucial role in the induction of experimental autoimmune encephalomyelitis

CCR7 on CD4+ T Cells Plays a Crucial Role in the Induction of Experimental Autoimmune Encephalomyelitis

Abstract Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Myelin-specific CD4+ Th lymphocytes are known to play a major role in both MS and its animal model experimental autoimmune encephalomyelitis (EAE). CCR7 is a critical element for immune cell trafficking and recirculation, that is, lymph node homing, under homeostatic conditions; blocking CCR7+ central memory cells from egress of lymph nodes is a therapeutic approach in MS. To define the effect of CD4+ T cell–specific constitutive deletion of CCR7 in the priming and effector phase in EAE, we used an active EAE approach in T cell reconstituted Rag1−/− mice, as well as adoptive transfer E…

Transmembrane BAX Inhibitor-1 Motif Containing Protein 5 (TMBIM5) Sustains Mitochondrial Structure, Shape, and Function by Impacting the Mitochondrial Protein Synthesis Machinery

The Transmembrane Bax Inhibitor-1 motif (TMBIM)-containing protein family is evolutionarily conserved and has been implicated in cell death susceptibility. The only member with a mitochondrial localization is TMBIM5 (also known as GHITM or MICS1), which affects cristae organization and associates with the Parkinson&rsquo

The Charcot Marie Tooth Disease Mutation R94Q in MFN2 Decreases ATP Production but Increases Mitochondrial Respiration under Conditions of Mild Oxidative Stress

Charcot-Marie tooth disease is a hereditary polyneuropathy caused by mutations in Mitofusin-2 (MFN2), a GTPase in the outer mitochondrial membrane involved in the regulation of mitochondrial fusion and bioenergetics. Autosomal-dominant inheritance of a R94Q mutation in MFN2 causes the axonal subtype 2A2A which is characterized by early onset and progressive atrophy of distal muscles caused by motoneuronal degeneration. Here, we studied mitochondrial shape, respiration, cytosolic, and mitochondrial ATP content as well as mitochondrial quality control in MFN2-deficient fibroblasts stably expressing wildtype or R94Q MFN2. Under normal culture conditions, R94Q cells had slightly more fragmented…

Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment.

Objective: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity. Methods: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients. Results: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untr…

The thiol switch C684 in Mitofusin-2 mediates redox-induced alterations of mitochondrial shape and respiration

Mitofusin-2 (MFN2) is a GTPase in the outer mitochondrial membrane involved in the regulation of mitochondrial fusion and bioenergetics. MFN2 also plays a role in mitochondrial fusion induced by changes in the intracellular redox state. Adding oxidized glutathione (GSSG), the core cellular stress indicator, to mitochondrial preparations stimulates mitochondrial fusion by inducing disulphide bond-mediated oligomer formation of MFN2 and its homolog MFN1 which involve cysteine 684 (C684) of MFN2. Mitochondrial hyperfusion represents an adaptive stress response that confers transient protection by increasing mitochondrial ATP production but how this depends on the thiol switch C684 in MFN2 has …

NECAB2 participates in an endosomal pathway of mitochondrial stress response at striatal synapses

Synaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control. We found that the neuronal calcium-binding protein NECAB2 ensures synaptic function in the striatum by increasing mitochondrial efficiency. NECAB2 associates with early endosomes and mitochondria at striatal synapses. Loss of NECAB2 dysregulates proteins of the endosomal ESCRT machinery and oxidative phosphorylation. Mitochondria from NECAB2-deficient mice are more abundant but less efficient. These mitochondria exhibit increased respiration and superoxide production but produ…