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Subclinical infection can be an initiator of inflammaging leading to degenerative disk disease: evidence from host-defense response mechanisms

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Abstract

Purpose

There is considerable controversy on the role of genetics, mechanical and environmental factors, and, recently, on subclinical infection in triggering inflammaging leading to disk degeneration. The present study investigated sequential molecular events in the host, analyzing proteome level changes that will reveal triggering factors of inflammaging and degeneration.

Methods

Ten MRI normal disks (ND) from braindead organ donors and 17 degenerated disks (DD) from surgery were subjected to in-gel-based label-free ESI-LC–MS/MS analysis. Bacterial-responsive host-defense response proteins/pathways leading to Inflammaging were identified and compared between ND and DD.

Results

Out of the 263 well-established host-defense response proteins (HDRPs), 243 proteins were identified, and 64 abundantly expressed HDRPs were analyzed further. Among the 21 HDRPs common to both ND and DD, complement factor 3 (C3) and heparan sulfate proteoglycan 2 (HSPG2) were significantly upregulated, and lysozyme (LYZ), superoxide dismutase 3 (SOD3), phospholipase-A2 (PLA2G2A), and tissue inhibitor of metalloproteinases 3 (TIMP-3) were downregulated in DD. Forty-two specific HDRPs mainly, complement proteins, apolipoproteins, and antimicrobial proteins involved in the complement cascade, neutrophil degranulation, and oxidative-stress regulation pathways representing an ongoing host response to subclinical infection and uncontrolled inflammation were identified in DD. Protein–Protein interaction analysis revealed cross talk between most of the expressed HDRPs, adding evidence to bacterial presence and stimulation of these defense pathways.

Conclusions

The predominance of HDRPs involved in complement cascades, neutrophil degranulation, and oxidative-stress regulation indicated an ongoing infection mediated inflammatory process in DD. Our study has documented increasing evidence for bacteria’s role in triggering the innate immune system leading to chronic inflammation and degenerative disk disease.

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Abbreviations

A1BG:

Alpha 1b glycoprotein

AMPs:

Antimicrobial proteins

ANIMO:

Analysis of Networks with Interactive MOdeling

APCS:

Serum amyloid P component

ARHGAP5:

Rho GTPase activating protein 5

AZU1:

Azurocidin

BRAF:

Proto-oncogene-B-rapidly accelerated fibrosarcoma

C3:

Complement component C3

C5:

Complement component C5

CA2:

Carbonic Anhydrase 2

CAMP:

Cathelicidin–antimicrobial–peptide

CAT:

Catalase

CFD:

Complement factor D

CFH:

Complement factor H

CHI3L1:

Chitinase–3–like–protein–1

CLR:

C-type lectin receptors

CLU:

Clusterin

CTSG:

Cathepsin G

DAMPs:

Disease-associated molecular patterns

DCD:

Dermcidin

DD:

Degenerated disks

DDD:

Degenerative disk disease

DEFA1:

Defensin–Alpha 1

ECM:

Extracellular matrix

ESI:

Electrospray ionization

GOnet:

Interactive tool for gene ontology analysis

HDRP:

Host-defense response proteins

HP:

Haptoglobin

HSPA8:

Heat shock 70 kDa protein A8

HSPG2:

Heparan sulfate proteoglycan 2/perlecan

ICMR:

Indian Council of Medical Research

IFN-γ:

Interferon gamma

IGHM:

Immunoglobulin heavy constant mu

IL-6:

Interleukin 6

IRB:

Institutional review Board

LC:

Liquid chromatography

LCN2:

Lipocalin 2

LGALS8:

Galectin 8

LL-37:

Active Form of CAMP precursor

LPS:

Lipopolysaccharide

LTA:

Lipoteichoic acid

LTF:

Lactotransferrin

LYZ:

Lysozyme

MAC:

Membrane attack complex

MAPK:

Mitogen–Activated protein kinase

MCP1:

Monocyte chemoattractant protein-1

MCP3:

Monocyte chemotactic protein 3

MPO:

Myeloperoxidase

MRI:

Magnetic resonance imaging

MS/MS:

Tandem mass spectrometry

ND:

Normal disks

NK cells:

Natural killer cells

NLR:

NOD-like receptors

NOD:

Nucleotide–binding oligomerization domain

PAMPs:

Pathogen-associated molecular patterns

PANTHER:

Protein annotation through evolutionary relationship

PGN:

Peptidoglycan

PLA2G2A:

Synovial phospholipase A2

PPI:

Protein–protein interaction

PRDX1:

Peroxiredoxin 1

PRDX2:

Peroxiredoxin 2

PRDX6:

Peroxiredoxin 6

PRR:

Pattern recognition receptors

PSM:

Peptide spectral match

RAF:

Rapidly accelerated fibrosarcoma

RAS:

Rat sarcoma

Reactome:

A database of reactions, pathways and biological processes

RLR:

Retinoic acid-inducible gene 1 like receptors

SOD3:

Extracellular superoxide dismutase

STRING:

Search tool for the retrieval of interacting genes/proteins

TCC:

Terminal complement complex

TIMP3:

Tissue inhibitor of metalloproteinase 3

TLR:

Toll–Like receptors

TNC:

Tenascin C

TNFAIP6:

Tumor necrosis factor-inducible gene 6 protein

TNFα:

Tumor necrosis factor alpha or cachexin, or cachectin

UPPAAL:

Tool for interactive modeling

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Acknowledgement

SR, SDCR, TC, and MR conceived and formulated the project. NSM, TC contributed to the design of the analysis; performed laboratory experiments and bulk of data analysis; SDCR, KSSV, KRM, and SAP wrote and prepared the manuscript. All authors have read through and given the final approval of the submitted publication. We also acknowledge the efforts of Ms M Sujitha and Ms M Dhanalakshmi for assistance in LC–MS/MS experiments.

Funding

The project was funded by Ganga Orthopaedic Research & Education Foundation (GOREF 2019–07).

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Authors and Affiliations

  1. Department of Orthopaedics and Spine Surgery, Ganga Hospital, 313, Mettupalayam road, Coimbatore, India

    S. Rajasekaran, S. Dilip Chand Raja, K. S. Sri Vijayanand, Shetty Ajoy Prasad & Kanna Rishi Mugesh

  2. Ganga Research Centre, No 91, Mettupalayam road, Coimbatore, 641030, India

    Tangavel Chitraa & Nayagam Sharon Miracle

  3. Department of Plant Biotechnology, Tamil Nadu Agricultural University, Coimbatore, 641003, India

    M. Raveendran

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Rajasekaran, S., Chitraa, T., Dilip Chand Raja, S. et al. Subclinical infection can be an initiator of inflammaging leading to degenerative disk disease: evidence from host-defense response mechanisms. Eur Spine J 30, 2586–2604 (2021). https://doi.org/10.1007/s00586-021-06826-z

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