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Distinct extracellular-matrix remodeling events precede symptoms of inflammation

ABSTRACT: Identification of early processes leading to complex tissue pathologies, such as inflammatory bowel diseases, poses a major scientific and clinical challenge that is imperative for improved diagnosis and treatment. Most studies of inflammation onset focus on cellular processes and signaling molecules, while overlooking the environment in which they take place, the continuously remodeled extracellular matrix. In this study, we used colitis models for investigating extracellular-matrix dynamics during disease onset, while treating the matrix as a complete and defined entity. Through the analysis of matrix structure, stiffness and composition, we unexpectedly revealed that even prior to the first clinical symptoms, the colon displays its own unique extracellular-matrix signature and found specific markers of clinical potential, which were also validated in human subjects. We also show that the emergence of this pre-symptomatic matrix is mediated by subclinical infiltration of immune cells bearing remodeling enzymes. Remarkably, whether the inflammation is chronic or acute, its matrix signature converges at pre-symptomatic states. We suggest that the existence of a pre-symptomatic extracellular-matrix is general and relevant to a wide range of diseases.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Colon

DISEASE(S): Crohn's Disease,Ulcerative Colitis

SUBMITTER: Idan Adir

LAB HEAD: Ulrich auf dem Keller

PROVIDER: PXD022668 | Pride | 2020-12-02

REPOSITORIES: Pride

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			Action	DRS
	20200309_MB_SS_Idan_DSS_NPO_500ng.msfView	Msf
	20200309_MB_SS_Idan_DSS_NPO_500ng.pdResult	Other
	20200309_MB_SS_Idan_DSS_NPO_500ng.pep.xml	Pepxml
	20200309_MB_SS_Idan_DSS_NPO_500ng.raw	Raw
	20200309_MB_SS_Idan_DSS_PO_500ng.msfView	Msf

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Project description:Proteases control complex tissue responses by modulating inflammation, cell proliferation and migration, and matrix remodeling. All these processes are orchestrated in cutaneous wound healing to restore the skinâ€™s barrier function upon injury. Altered protease activity has been implicated in the pathogenesis of healing impairments, and proteases are important targets in diagnosis and therapy of this pathology. Global assessment of proteolysis at critical turning points after injury will define crucial events in acute healing that might be disturbed in healing disorders. As optimal biospecimens, wound exudates contain an ideal proteome to detect extracellular proteolytic events, are non-invasively accessible, and can be collected at multiple time points along the healing process from the same wound in the clinics. In this study, we applied multiplexed Terminal Amine Isotopic Labeling of Substrates (TAILS) to globally assess proteolysis in early phases of cutaneous wound healing. By quantitative analysis of proteins and protein N termini in wound fluids from a clinically relevant pig wound model, we identified more than 650 proteins and discerned major healing phases through distinctive abundance clustering of markers of inflammation, granulation tissue formation, and re-epithelialization. TAILS revealed a high degree of proteolysis at all time points after injury by detecting almost 1300 N-terminal peptides in ~450 proteins, most of which could not be assigned to known mature protein N termini. Quantitative positional proteomics mapped pivotal interdependent processing events in the blood coagulation cascade, detailed activating thrombin cleavages in vivo, and temporally discerned clotting and fibrinolysis during the healing process. Similarly, we found virtually all major cleavages in complement activation and inactivation and demonstrated time-dependent changes in the proteolytic potential of the wound milieu by detecting processing of complement C3 at distinct time points after wounding and by different proteases.

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Distinct extracellular-matrix remodeling events precede symptoms of inflammation

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