Cochlin Produced by Follicular Dendritic Cells Promotes Antibacterial Innate Immunity

Py, Bénédicte F.; González, Santiago F.; Long, Kai; Kim, Mi-Sung; Kim, Young-A; Zhu, Hong; Yao, Jianhua; Degauque, Nicolas; Villet, Régis; Ymele-Leki, Patrick; Gadjeva, Mihaela; Pier, Gerald B.; Carroll, Michael; Yuan, Junying

doi:10.1016/j.immuni.2013.01.015

Cited by 61 publications

(92 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…regulation, presumably because known mutations in the COCH gene are rare and genotype-phenotype correlations have not been extensively investigated (16,17).…”

Section: Significancementioning

confidence: 99%

“…Although cues from the ECM determine functions in many organs, its role in immunity is less well understood. Evidence is emerging that the ECM in lymphoid organs, in addition to its obvious scaffold functions (12)(13)(14)(15), can also directly instruct mature immune cells (16). In this context, cochlin-an ECM protein with expression restricted to cochlea, lymph nodes, and spleen (16)-is of high interest.…”

mentioning

confidence: 99%

“…The physiological function of cochlin still needs elucidation, but cochlin has been suggested to be involved in mechanosensing, as well as being a local and systemic regulator of antibacterial immunity (16,18,19). Cochlin-deficient mice show impaired abilities to clear experimentally induced lung infection with Pseudomonas aeruginosa and Staphylococcus aureus (16).…”

mentioning

confidence: 99%

“…In lymph nodes and spleen, cochlin is sequestered in lymphoid conduits (16), tube-like ECM structures composed of a collagen core surrounded by a microfibril layer and a basement membrane (20,21). The molecular composition of conduits varies between the distinct areas of the splenic white pulp (15,(20)(21)(22), pointing to differentiated roles of individual ECM components in regulating specific immune reactions (15).…”

mentioning

confidence: 99%

“…In response to bacterial infection, aggrecanase-mediated processing of cochlin, sequestered in the lumen of follicular conduits, leads to systemic increase of the cochlin LCCL domain. This, in turn, activates macrophages and neutrophils peripherally and thereby stimulates bacterial clearance at infection sites (16). The mechanism of this activation is currently not completely understood, So far, no human disease has been attributed to this line of immune…”

mentioning

confidence: 99%

See 4 more Smart Citations

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.collagen VII | innate immunity | bacteria | recessive dystrophic epidermolysis bullosa | cochlin

show abstract

“…regulation, presumably because known mutations in the COCH gene are rare and genotype-phenotype correlations have not been extensively investigated (16,17).…”

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Nyström

Bornert

Kühl

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

Identification of Pathogenic Mechanisms ofCOCHMutations, Abolished Cochlin Secretion, and Intracellular Aggregate Formation: Genotype-Phenotype Correlations in DFNA9 Deafness and Vestibular Disorder

et al. 2014

View full text Add to dashboard Cite

Mutations in COCH cause autosomal dominant non-syndromic hearing loss with variable degrees of clinical onset and vestibular malfunction. We selected eight uncharacterized mutations and performed immunocytochemical and Western blot analyses to track cochlin through the secretory pathway. We then performed a comprehensive analysis of clinical information from DFNA9 patients with all 21 known COCH mutations in conjunction with cellular and molecular findings to identify genotype-phenotype correlations. Our studies revealed that five mutants were not secreted into the media: two vWFA domain mutants, which were not transported from the ER to Golgi complex and formed high-molecular-weight aggregates in cell lysates; and three LCCL domain mutants, which were detected as intracellular dimeric cochlins. Mutant cochlins that were not secreted and accumulated in cells result in earlier age of onset of hearing defects. In addition, individuals with LCCL domain mutations show accompanying vestibular dysfunction, whereas those with vWFA domain mutations exhibit predominantly hearing loss. This is the first report showing failure of mutant cochlin transport through the secretory pathway, abolishment of cochlin secretion, and formation and retention of dimers and large multimeric intracellular aggregates, and high correlation with earlier onset and progression of hearing loss in individuals with these DFNA9-causing mutations.

show abstract

NovelCOCHp.V123E Mutation, Causative of DFNA9 Sensorineural Hearing Loss and Vestibular Disorder, Shows Impaired Cochlin Post-Translational Cleavage and Secretion

et al. 2015

View full text Add to dashboard Cite

DFNA9 is an autosomal dominant disorder characterized by late-onset, non-syndromic hearing loss, and vestibular dysfunction. Mutations in the COCH (coagulation factor C homology) gene encoding cochlin are etiologically linked to DFNA9. Previous studies have shown that cochlin is cleaved by aggrecanase-1 during inflammation in the spleen and that the cleaved LCCL domain functions as an innate immune mediator. However, the physiological role of cochlin in the inner ear is not completely understood. Here, we report that cochlins containing DFNA9-linked mutations (p.P51S, p.V66G, p.G88E, p.I109T, p.W117R, p.V123E, and p.C162Y) demonstrate reduced cleavage by aggrecanase. Notably, in families affected with DFNA9, we found a novel COCH mutation causing p.V123E substitution in cochlin, which significantly reduced protein susceptibility to cleavage by aggrecanase (to about 20.5% of the wild-type). These results suggest that the impaired post-translational cleavage of cochlin mutants may be associated with pathological mechanisms underlying DFNA9-related sensorineural hearing loss.

show abstract

Cochlin Produced by Follicular Dendritic Cells Promotes Antibacterial Innate Immunity

Cited by 61 publications

References 44 publications

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

Identification of Pathogenic Mechanisms ofCOCHMutations, Abolished Cochlin Secretion, and Intracellular Aggregate Formation: Genotype-Phenotype Correlations in DFNA9 Deafness and Vestibular Disorder

NovelCOCHp.V123E Mutation, Causative of DFNA9 Sensorineural Hearing Loss and Vestibular Disorder, Shows Impaired Cochlin Post-Translational Cleavage and Secretion

Contact Info

Product

Resources

About