Inflammatory cell death in intestinal pathologies

Abstract

Summary The intestinal tract is a site of intense immune cell activity that is poised to mount an effective response against a pathogen and yet maintain tolerance towards commensal bacteria and innocuous dietary antigens. The role of cell death in gut pathologies is particularly important as the intestinal epithelium undergoes self-renewal every four to seven days through a continuous process of cell death and cell division. Cell death is also required for removal of infected, damaged and cancerous cells. Certain forms of cell death trigger inflammation through release of damage associated molecular patterns (DAMPs). Further, molecules involved in cell-death decisions also moonlight as critical nodes in immune signaling. The manner of cell death is, therefore, highly instructive of the immunological consequences that ensue. Perturbations in cell death pathways can impact the regulation of the immune system with deleterious consequences. In this review, we discuss the various forms of cell death with a special emphasis on lytic cell death pathways of pyroptosis and necroptosis and their implications in inflammation and cancer in the gut. Understanding the implications of distinct cell death pathways will help in the development of therapeutic interventions in intestinal pathologies.

TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy

“…Further, the pathogenic role of TNF in Mefv V726A/V726A mice is mediated through TNFR1 while TNFR2 signaling is protective against certain pathologies, including arthritis and colitis. TNF/TNFR1 signaling is involved in proinflammatory cytokine production through NF-κB and MAPK activation and in proapoptotic signaling through the RIPK3/CASP8 axis (63). We have previously shown that, unlike TNFR1 signaling, lack of the While the loss of TNF/TNFR signaling provided substantial protection against all disease characteristics, it was particularly effective against neutrophilia.…”

Effects of alpha lipoic acid and its derivative “andrographolid‐lipoic acid‐1” on ulcerative colitis: A systematic review with meta‐analysis of animal studies

“…55 The attachment of TNF-α to its receptor (TNF-α R) triggered a specific downstream cascade, to facilitate the nucleus translocation of the transcription factor NF-κB and other inflammatory factors, such as TNF-α and IL-6. 57 Indeed, ALA interacted with phosphorylation of IkB-α as an NF-κB suppressant within the cytoplasm by means of either mitogen-activated protein kinase (MAPK) or recycling of vitamin E ( Figure 5). NF-κB-mediated gene transcription and/or translation was vital to regulate the intestinal cell death and to maintain the intestinal homeostasis.…”

“…It was evident that the intestinal cell death and homeostasis have been significantly implicated in chronic colitis. 57 Indeed, ALA interacted with phosphorylation of IkB-α as an NF-κB suppressant within the cytoplasm by means of either mitogen-activated protein kinase (MAPK) or recycling of vitamin E ( Figure 5). 12 On the contrary, subsequent to trimerization of TNF-α receptor, and recruitment of TNF receptor-associated factor-2 (TRAF-2) and ribosome inactivating protein (RIP) to death domain (DD), both of the TNF receptor type 1-associated DD protein (TRADD), TNF-α R, and IkB kinase (IKKs) were stimulated either directly [58][59][60][61] ( Figure 5) or indirectly via MAPK kinase 1-MAPK kinase 4-IKK (MEKK1-MKK4-IKK) pathway, which was stymied by ALA at each stage ( Figure 5).…”

Death, danger & immunity: Fundamental mechanisms linking pathogenic or iatrogenic cell death events to immune responses

“…It is only when cell death occurs at a massive scale and when it is induced by non‐physiological stimuli such as infectious pathogens, chemical agents, or irradiation that it results in inflammatory or immune reactions that have an impact on whole‐body physiology . The present issue of Immunological Review is dealing with the mechanistic links between Death, Danger and Immunity .…”

“…2 It is only when cell death occurs at a massive scale and when it is induced by non-physiological stimuli such as infectious pathogens, chemical agents, or irradiation that it results in inflammatory or immune reactions that have an impact on whole-body physiology. 3,4 The present issue of Immunological Review is dealing with the mechanistic links between Death, Danger and Immunity. Thus, major emphasis is laid on the danger signals that emanate from stressed and dying cells as dangerassociated molecular patterns (DAMPs) or cell death-associated molecular patterns (CDAMPs) and that in fine determine whether cell death results in inflammatory and immune responses or not ( Figure 1).…”