PANoptosis is an inflammatory cell death pathway. Consideration of the totality of biological effects from cell death in multiple studies has led to the conceptualization of PANoptosis, a unique innate immune inflammatory cell death pathway regulated by multifaceted PANoptosome complexes that have been visualized in single cells to integrate components from other cell death pathways. PANoptosis is implicated in driving innate immune responses and inflammation and cannot be individually accounted for by

pyroptosis Pyroptosis is a highly inflammatory form of Lysis, lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearanc ...

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

, or

necroptosis Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell dea ...

alone. PANoptosome formation and PANoptosis occur during pathogenic infections, including bacterial, viral, and fungal infections, as well as during inflammatory diseases and can be beneficial in the context of cancer. Inflammatory cell death is associated with activation of the immune system through the release of

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s and

damage-associated molecular pattern Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger-associated m ...

s. Live pathogens that carry multiple

pathogen-associated molecular pattern Pathogen-associated molecular patterns (PAMPs) are small molecular motifs conserved within a class of microbes. They are recognized by toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) in both plants and animals. A vast arra ...

s and homeostasis-altering triggers can modulate cell death pathways.

Pyroptosis Pyroptosis is a highly inflammatory form of Lysis, lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearanc ...

(inflammatory caspase-mediated cell death that drives maturation of the cytokines

IL-1β Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the ''IL1B'' gene."Catabolin" ...

and IL-18) and

(RIPK1/RIPK3/MLKL-driven cell death) were historically described as two major inflammatory cell death pathways, with recent studies describing PANoptosis as an additional inflammatory cell death pathway. Activation of PANoptosis can clear infected cells for host defense, and it has shown preclinical promise as an anti-cancer strategy. For example, PANoptosis is important for host defense during

influenza Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...

, ''

Francisella ''Francisella'' is a genus of Gram-negative bacteria. They are small coccobacillary or rod-shaped, nonmotile organisms, which are also facultative intracellular parasites of macrophages. Strict aerobes, ''Francisella'' colonies bear a morpholog ...

'', and

herpes simplex virus 1 Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...

infections. Additionally, treatment of cancer cells with the PANoptosis-inducing agents TNF and IFN-γ can reduce tumor size in preclinical models. The combination of the nuclear export inhibitor

selinexor Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in ...

and

IFN Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...

can also cause PANoptosis and regress tumors in preclinical models. However, excess activation of PANoptosis can be associated with inflammation, inflammatory disease, and cytokine storm syndromes.{{Cite journal, last=Karki, first=Rajendra, last2=Kanneganti, first2=Thirumala-Devi, date=August 2021, title=The 'cytokine storm': molecular mechanisms and therapeutic prospects, url=https://pubmed.ncbi.nlm.nih.gov/34217595, journal=Trends in Immunology, volume=42, issue=8, pages=681–705, doi=10.1016/j.it.2021.06.001, issn=1471-4981, pmid=34217595 Treatments that block TNF and IFN-γ to prevent PANoptosis have provided therapeutic benefit in preclinical models of cytokine storm syndromes, including cytokine shock,

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...

infection,

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

, and

hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH), also known as haemophagocytic lymphohistiocytosis (British spelling), and hemophagocytic or haemophagocytic syndrome, is an uncommon hematologic disorder seen more often in children than in adults. It is a ...

, suggesting the therapeutic potential of modulating this pathway. Further studies with beta-coronaviruses have shown that IFN can induce

ZBP1 Z-DNA-binding protein 1, also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1, is a protein that in humans is encoded by the ''ZBP1'' gene. ZBP1 is also an abbreviation for chicken or rat β-actin zipcode-binding protei ...

-mediated PANoptosis during SARS-CoV-2 infection, thereby limiting the efficacy of IFN treatment during infection and resulting in morbidity and mortality. This suggests that inhibiting ZBP1 may improve the therapeutic efficacy of IFN therapy during SARS-CoV-2 infection and possibly other inflammatory conditions where IFN-mediated cell death and pathology occur.

References

Cell biology