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Regulation of inflammatory processes by caspases

Abstract

Historically, mammalian caspases (a group of cysteine proteases) have been catalogued into two main families based on major biological function: inflammatory caspases and apoptotic caspases. Accumulating evidence from preclinical models, however, argues against such a clearcut distinction, for two main reasons. First, at least in mammals, apoptotic caspases are generally dispensable for cells to succumb to apoptotic stimuli but instead regulate the kinetic and microenvironmental manifestations of the cellular demise in the context of a complex interplay with other cell death pathways. Second, most (if not all) mammalian caspases have evolved into positive or negative regulators of inflammatory processes, either directly or via their ability to control apoptotic and non-apoptotic cell death modalities. Here we discuss the molecular mechanisms through which mammalian caspases regulate inflammation, with emphasis on the ability of apoptotic caspases to suppress inflammatory responses in support of preserved organismal homeostasis.

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Fig. 1: Pro-inflammatory caspases.
Fig. 2: Roles of caspase 8 in cell death and inflammation.
Fig. 3: MOMP-activated caspases.

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Acknowledgements

K.A.S., D.R.G. and L.G. are grateful to the William Guy Forbeck Research Foundation for fostering the dissemination of knowledge, promoting scientific collaboration and supporting the training of the next generation of leaders in cancer research. D.R.G. acknowledges the support (as a PI unless otherwise indicated) of two R01 grants from the NIH/NCI (nos. CA231620 and AI44828). Among other sources, L.G. acknowledges the support (as a PI unless otherwise indicated) of one R01 grant from the NIH/NCI (no. CA271915); two Breakthrough Level 2 grants from the US DoD BCRP (nos. BC180476P1 and BC210945); a grant from the STARR Cancer Consortium (no. I16-0064); a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (no. W81XWH2120034, PI: Formenti); a U54 grant from NIH/NCI (no. CA274291, PI: Deasy, Formenti, Weichselbaum); the 2019 Laura Ziskin Prize in Translational Research (no. ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C); a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukaemia and Lymphoma Society; a Rapid Response Grant from the Functional Genomics Initiative (New York, USA); a pre-SPORE grant (PI: Demaria, Formenti); a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center (New York, USA); as well as startup funds from the Department of Radiation Oncology at Weill Cornell Medicine (New York, USA) and Fox Chase Cancer Center (Philadelphia, PA).

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L.G., M.B.-V. and R.S.-A. researched data for the article. All authors contributed substantially to discussion of the content. L.G., M.B.-V. and R.S.-A. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Lorenzo Galluzzi.

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D.R.G. is/has been holding research contracts with Amgen and has received consulting/advisory honoraria for Sonata Pharmaceuticals, Ventus Pharmaceuticals and ASHA Therapeutics. L.G. is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo, has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, AbbVie and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. The other authors have no conflicts of interest to declare.

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Glossary

ADP-riboxanation

A complex post-translational modification that involves Arg residues and can affect protein functionality.

Antigen-presenting cells

Myeloid or lymphoid cells that are capable of engulfing and processing antigenic material for presentation to T lymphocytes.

Apoptosome

An APAF1-dependent multiprotein complex that enables the activation of caspase 9 in response to mitochondrial outer membrane permeabilization.

Autoimmune lymphoproliferative syndrome

A rare genetic disorder characterized by lymphoproliferation, autoimmune disease and an increased propensity to develop certain tumours.

Autophagic machinery

The molecular machinery responsible for a lysosome-dependent catabolic pathway that disposes of superfluous, exogenous or potentially toxic cytosolic entities, including invading pathogens and permeabilized mitochondria.

Canonical inflammasomes

Cytosolic multiprotein complex that enable the activation of caspase 1 and the consequent release of mature IL-1β and IL-18, coupled with GSDMD-dependent pyroptosis in response to various inflammatory cues.

Cornified epithelium

The outermost layer of the skin and other stratified epithelia that forms through the death and keratinization of epithelial cells.

Damage-associated molecular patterns

(DAMPs). Cell damage can cause these endogenous molecules to become exposed on the cell surface or secreted into the extracellular environment, where they interact with immune cells and mediate robust inflammatory effects.

Dendritic cells

Myeloid cells that operate at the interface between innate and adaptive immune responses, by presenting antigenic material to T lymphocytes.

Immunogenic cell death

A form of regulated cell death that is sufficient (in immunocompetent syngeneic hosts) to initiate adaptive immune responses targeting dead cell-associated antigens.

Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

(MPTP). An organic compound of the tetrahydropyridine family that is commonly used to induce Parkinson disease in research animals.

Natural killer cell

A lymphoid cell that mediates antigen-independent cytotoxic and secretory functions upon recognition of distress signals on infected or malignant cells.

Necroptosis

A form of regulated necrosis that relies on plasma membrane permeabilization by MLKL.

Neutrophil extracellular traps

(NETs). Networks of extracellular fibres containing decondensed DNA and lytic proteins that are released by dying neutrophils in response to pathogen exposure.

Non-canonical inflammasome

A cytosolic multiprotein complex that enables the activation of caspase 4, caspase 5 or caspase 11 in response to intracellular LPS from Gram-negative bacteria, resulting in pyroptotic cell death and secondary activation of canonical inflammasomes.

Phosphatidylserine

A phospholipid of the inner leaflet of the plasma membrane that is rapidly externalized during apoptotic cell death as a signal for efferocytosis.

Regulatory T cells

Immunosuppressive T lymphocytes that are fundamental to prevent self-reactive lymphocytes in the periphery from causing autoimmunity.

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Beltrán-Visiedo, M., Soler-Agesta, R., Sarosiek, K.A. et al. Regulation of inflammatory processes by caspases. Nat Rev Mol Cell Biol (2025). https://doi.org/10.1038/s41580-025-00869-6

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