Dataset Information

Aggregation as a host defense mechanism

ABSTRACT: In this work, we hypothesized that the aggregation of proteins during wounding is a physiological host defense mechanism, which is triggered during pathogen invasion. Here, we demonstrate the ability of acute wound fluids (AWFs) to aggregate their protein content after exposer to bacterial endotoxins such as lipopolysaccharides (LPS). The composition of LPS-triggered aggregates clearly shows the enrichment of specific protein families, which are for example involved in the immune system, coagulation cascade, nuclear matrix, or lipid metabolism.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Wound Fluid, Wound Healing Involved In Inflammatory Response

DISEASE(S): Wounds And Injuries

SUBMITTER: Charlotte Welinder

LAB HEAD: Jitka Petrlova

PROVIDER: PXD030521 | Pride | 2023-10-12

REPOSITORIES: Pride

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Publications

Selective protein aggregation confines and inhibits endotoxins in wounds: Linking host defense to amyloid formation.

Petrlova Jitka J Hartman Erik E Petruk Ganna G Lim Jeremy Chun Hwee JCH Adav Sunil Shankar SS Kjellström Sven S Puthia Manoj M Schmidtchen Artur A

iScience 20230919 10

Bacterial lipopolysaccharide (LPS) induces rapid protein aggregation in human wound fluid. We aimed to characterize these LPS-induced aggregates and their functional implications using a combination of mass spectrometry analyses, biochemical assays, biological imaging, cell experiments, and animal models. The wound-fluid aggregates encompass diverse protein classes, including sequences from coagulation factors, annexins, histones, antimicrobial proteins/peptides, and apolipoproteins. We identifi ...[more]

PMID: 37817942

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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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