ABSTRACT
Lymphedema (LD) is characterized by the accumulation of interstitial fluid, lipids and inflammatory cell infiltrate in the limb. Here, we find that LD tissues from women who developed LD after breast cancer exhibit an inflamed gene expression profile. Lipidomic analysis reveals decrease in specialized pro-resolving mediators (SPM) generated by the 15-lipoxygenase (15-LO) in LD. In mice, the loss of SPM is associated with an increase in apoptotic regulatory T (Treg) cell number. In addition, the selective depletion of 15-LO in the lymphatic endothelium induces an aggravation of LD that can be rescued by Treg cell adoptive transfer or ALOX15-expressing lentivector injections. Mechanistically, exogenous injections of the pro-resolving cytokine IFN-ß restores both 15-LO expression and Treg cell number in a mouse model of LD. These results provide evidence that lymphatic 15-LO may represent a therapeutic target for LD by serving as a mediator of Treg cell populations to resolve inflammation.
Subject(s)
Arachidonate 15-Lipoxygenase , Lymphedema , Humans , Mice , Female , Animals , Arachidonate 15-Lipoxygenase/genetics , Arachidonate 15-Lipoxygenase/metabolism , Inflammation/metabolism , Cytokines/metabolism , T-Lymphocytes, Regulatory/metabolismABSTRACT
The formation of the neuromuscular junction (NMJ) is directed by reciprocal interactions between motor neurons and muscle fibers. Neuregulin (NRG) and Agrin from motor nerve terminals are both implicated. Here, we demonstrate that NMJs can form in the absence of the NRG receptors ErbB2 and ErbB4 in mouse muscle. Postsynaptic differentiation is, however, induced by Agrin. We therefore conclude that NRG signaling to muscle is not required for NMJ formation. The effects of NRG signaling to muscle may be mediated indirectly through Schwann cells.
Subject(s)
ErbB Receptors/physiology , Muscle, Skeletal/innervation , Neuregulins/metabolism , Neuromuscular Junction/physiology , Receptor, ErbB-2/physiology , Signal Transduction , Agrin/physiology , Animals , Animals, Newborn , Cells, Cultured , ErbB Receptors/genetics , Genes, erbB , Genes, erbB-2 , Membrane Potentials , Mice , Motor Endplate/metabolism , Motor Endplate/physiology , Motor Endplate/ultrastructure , Muscle, Skeletal/ultrastructure , Mutation , Neuromuscular Junction/embryology , Neuromuscular Junction/metabolism , Neuromuscular Junction/ultrastructure , Presynaptic Terminals/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, ErbB-2/genetics , Receptor, ErbB-4 , Receptors, Cholinergic/chemistry , Receptors, Cholinergic/genetics , Receptors, Cholinergic/metabolism , Recombination, Genetic , Schwann Cells/physiology , Synaptic TransmissionABSTRACT
Lipocalins are carrier proteins for hydrophobic molecules in many biological fluids. In the oral sphere (nasal mucus, saliva, tears), they have an environmental biosensor function and are involved in the detection of odours and pheromones. Herein, we report the first identification of human lipocalins involved in odorant binding. They correspond to a gene family located on human chromosome 9q34 produced by genomic duplications: two new odorant-binding protein genes ( hOBP (IIa) and hOBP (IIb) ), the previously described tear lipocalin LCN1 gene and two new LCN1 pseudogenes. Although 95% similar in sequence, the two hOBP (II) genes were differentially expressed in secretory structures. hOBP (IIa) was strongly expressed in the nasal structures, salivary and lachrymal glands, and lung, therefore having an oral sphere profile. hOBP (IIb) was more strongly expressed in genital sphere organs such as the prostate and mammary glands. Both were expressed in the male deferent ducts and placenta. Surprisingly, alternatively spliced mRNAs resulting in proteins with different C-termini were generated from each of the two genes. The single LCN1 gene in humans generated a putative odorant-binding protein in nasal structures. Finally, based on the proposed successive genomic duplication history, we demonstrated the recruitment of exons within intronic DNA generating diversity. This is consistent with a positive selection pressure in vertebrate evolution in the intron-late hypothesis.
Subject(s)
Carrier Proteins/genetics , Chromosomes, Human, Pair 9/genetics , Gene Duplication , Genitalia/metabolism , Mouth/metabolism , Multigene Family/genetics , Receptors, Odorant/genetics , Alternative Splicing/genetics , Amino Acid Sequence , Base Sequence , Carrier Proteins/biosynthesis , Carrier Proteins/chemistry , Carrier Proteins/metabolism , Chromosome Mapping , Female , Gene Expression Regulation/genetics , Humans , Lipocalin 1 , Lipocalins , Male , Molecular Sequence Data , Organ Specificity , Receptors, Odorant/biosynthesis , Receptors, Odorant/isolation & purification , Sequence Homology, Nucleic AcidABSTRACT
LCN1 gene encodes the tear lipocalin; the lipocalins are a large and growing family of proteins characterized by their ability to bind small hydrophobic molecules. We report here the location of a dinucleotide repeat microsatellite marker (D9S1826) close to LCN1 gene. Using the CEPH reference families, the position of LCN1 is located within the 9q34 genetic map between D9S23 and D9S158.