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: ECM disorganization; HMGB-1; Incisional hernia; pathogenesis; sterile inflammation.

Figure 1:

Sequential phases of normal wound healing process

Figure 2:

Potential locations on wound healing timeline for ECM disorganization and development of IH

Figure 3:

Inflammatory response due to the signaling cascade when HMGB-1 interacts with surface receptors TLR2/TLR4, TREM1, and RAGE. Upon interacting with TLR2/4, HMGB-1 activates the MyD88, or TRIF only for TLR4 and results in the upregulation of NF-κB, c-fos, and AP-1, which are inflammatory cytokines. When HMGB-1 interacts with TREM1, the DAP12 or ITAM pathway is triggered and results in the activation of inflammatory cytokines, c-fos, ELK1, and NF-κB, and it results in the inhibition of apoptosis. Finally, when HMGB-1 interacts with RAGE the m-Di9–1 pathway is activated. This results in NF-κB and AP-1 upregulation and enhancing the inflammatory response. Ultimately, the synergistic interactions of HMGB-1 and these surface receptors results in the increase of the inflammatory response and causes ECM disorganization.