Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa.

Abstract

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.

• Authors: Alexander Nyström, Olivier Bornert, Tobias Kühl, Christine Gretzmeier, Kerstin Thriene, Jörn Dengjel, Andrea Pfister-Wartha, Dimitra Kiritsi, Leena Bruckner-Tuderman
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 4 Pg. E705-E714 (01 23 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29305555 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• COCH protein, human
• Coch protein, mouse
• Collagen Type VII
• Extracellular Matrix Proteins

Topics

• Animals
• Collagen Type VII (physiology)
• Disease Models, Animal
• Epidermolysis Bullosa Dystrophica (immunology)
• Extracellular Matrix (immunology)
• Extracellular Matrix Proteins (metabolism)
• Humans
• Immunity, Innate
• Lymphoid Tissue (metabolism)
• Mice, Knockout
• Skin (microbiology)