Novel understanding of high mobility group box-1 in the immunopathogenesis of incisional hernias

ABSTRACT

Introduction: Incisional hernias (IH) arise as a complication of patients undergoing laparotomy. Current literature has assessed the role of extracellular matrix (ECM) disorganization, alterations in type I and type III collagen, matrix metalloproteinases, and tissue inhibitors of metalloproteases on IH. However, there is limited information on the underlying molecular mechanisms that lead to ECM disorganization.

Areas covered: We critically reviewed the literature surrounding IH and ECM disorganization and offer a novel pathway that may be the underlying mechanism resulting in ECM disorganization and the immunopathogenesis of IH.

Expert opinion: High mobility group box-1 (HMGB-1), a damage-associated molecular pattern, plays an important role in the sterile inflammatory pathway and has been linked to ECM disorganization and the triggering of the NLRP3 inflammasome. Further research to investigate the role of HMGB-1 in the molecular pathogenesis of IH would be critical in identifying novel therapeutic targets in the management of IH formation.

KEYWORDS:

• Incisional hernia
• pathogenesis
• ECM disorganization
• HMGB-1
• sterile inflammation

Article Highlights

• Incisional hernias (IH) are a complication of patients undergoing laparotomy and many risk factors have been correlated with the development of IH, technical factors at the initial operation and patient-related factors, but few studies have evaluated the underlying molecular mechanism.

• Current literature has evaluated the roles extracellular matrix (ECM) disorganization, alterations in type I and type III collagen, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteases (TIMPs) on IH. However, few studies have investigated the underlying molecular mechanism leading to ECM disorganization. In this review, we offer a novel pathway that may lead to the development of IH.

• HMGB-1 is an important damage-associated molecular pattern that is associated with sterile inflammation and responds to events caused by hypoxia and necrosis. HMGB-1 interacts with many surface molecules and receptors, specifically toll-like receptors 2 and 4 (TLR2 and TLR4), triggering receptors expressed on myeloid cells-1 (TREM-1), and receptor for advanced glycation end products (RAGE) and this binding results in a signaling cascade that leads to an inflammatory response via NF-κB, ELK1, c-fos, and AP-1.

• In addition to interacting with these receptors, HMGB-1 can aid in the assembly and activation of the NLRP3 inflammasome, which releases the pro-inflammatory cytokines of IL-1β and IL-18 that lead to ECM disorganization.

• If HMGB-1 and the resulting receptor interactions are identified in patients with IH, further study is warranted to examine the role of HMGB-1 on ECM disorganization and to elucidate this pathway in animal and human IH tissue. The findings may suggest several novel therapeutic modalities to inhibit NLRP3 assembly in patients with IH and prevent ECM disorganization.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The research work of DK Agrawal is supported by research grants R01 HL120659, and R01 HL144125 from the National Institutes of Health, USA. The content of this review article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.