Types of necroinflammation, the effect of cell death modalities on sterile inflammation.

DAMPs are typically derived from dying cells, although DAMPs can be released from living cells exposed to severe stress or by damage of extracellular matrix proteins [ 34 ]. Secretory lysosomes and exosomes also have been published as carriers of DAMPs during their active release such as HMGB1, ATP, histones, HSPs, RNAs and DNA [ 9 ]. DAMP release during cell death does not automatically initiate inflammation, only the activation of tissue-resident sensory cells (primarily macrophages and DCs) results in the production of inflammatory mediators. Sterile inflammation should be considered as a multi-step process [ 1 ]. Various, frequently unknown stimuli induce cell death [ 2 ], inflammatory forms of cell death results in DAMP or SAMP secretion, which is detected mostly by innate immune cells [ 3 ]. Activated cells produce cytokines, inflammatory and pro-resolving mediators, among them newly appeared DAMPs and SAMPs [ 4 , 35 , 36 ]. Some of these mediators have an autocrine effect on innate immune cells and some can also induce cell death [ 4 ]. In this complex process, DAMPs and SAMPs of dying cells and mediators released by innate immune cells altogether determine whether inflammation can progress into a chronic reaction, or the resolving of inflammation and tissue regeneration are induced. The exact individual role of most DAMPs in inflammation is not yet clear, but it can be hypothesized that simultaneous detection of different DAMPs may significantly amplify the danger signal, since it was described that after the activation of TLR receptors the interaction of several receptors may elicit a synergistic effect [ 37 ]. With this in mind, the diversity, amount, and half-life of DAMP/SAMP released from dying cells and the balance of mediator secreted efferocytes both influence subsequent reactions [ 38 ].

Are there precise subtypes of necroinflammation? Can the types of necroinflammation be related to the Th1, Th2, Th17 classification system? Do specific regulated cell death pathways trigger different types of necroinflammation? Are there precise subtypes of necroinflammation? Can the types of necroinflammation be related to the Th1, Th2, Th17 classification system? Do specific regulated cell death pathways trigger different types of necroinflammation?

Significantly different molecular mechanisms regulate the release of DAMPs in each regulated cell death process. Different DAMPs, cytokines and chemokines are released during various regulated cell death processes. Cell death processes have different effects on the differentiation of Th and ILC cell subpopulations. Significantly different molecular mechanisms regulate the release of DAMPs in each regulated cell death process. Different DAMPs, cytokines and chemokines are released during various regulated cell death processes. Cell death processes have different effects on the differentiation of Th and ILC cell subpopulations.

As we detailed above, cell death processes are characterized by different signal transduction pathways, execution mechanisms and various secretory routes for DAMP release. Necroinflammation induced by dying cells can lead to the release of different qualities and quantities of DAMPs/SAMPs. The characteristic secretory DAMP pattern for each cell death mode has not yet been systematically studied, and only a few comparative studies are available where DAMPs secreted by different cell death pathways are compared. In Table 2 , we collected the available data on which cell death modality leads to which DAMP production. The cell death-specific classification of individual DAMPs is complicated by the facts that secreted DAMPs/SAMPs may change over time during death processes, that cell death procedures can be progressive or even parallel events [ 36 ], and different subtypes of a particular cell death pathway may modify the immunological outcome of the processes [ 10 , 39 ]. Table 2 DAMPs and SAMPs released in different cell death forms. Apoptosis Necroptosis Pyroptosis Ferroptosis DAMPs • HMGB1 [ 10 ] • ATP [ 9 ] • DNA [ 9 ] • IL-1α [ 132 ] • IL-33 [ 120 ] • Histones [ 10 ] • RNA [ 9 ] • S100 proteins [ 133 ] • HSPs [ 134 ] • Uric acid [ 135 ] • mtDNA [ 136 ] • EMAP II [ 137 ] • Low molecular weight nucleotides [ 10 ] • HMGB1 [ 132 ] • ATP [ 10 ] • DNA [ 9 ] • IL-1α [ 132 ] • IL-33 [ 10 ] • Histones [ 10 ] • RNA [ 9 ] • S100A9 [ 10 ] • HSPs [ 9 ] • Uric acid [ 138 ] • mtDNA [ 10 ] • Long genomic DNA [ 138 ] • CIRP [ 9 ] • Cyclophilin A [ 139 ] • Spliceosome-associated Protein 130 [ 140 ] • HMGB1 [ 132 ] • ATP [ 9 ] • DNA [ 9 ] • IL-1α [ 132 ] • IL-1β [ 132 ] • IL-18 [ 132 ] • IL-33 [ 132 ] • mtDNA [ 132 ] • eCIRP [ 141 ] • ASC specks [ 10 ] • HMGB1 [ 9 ] • ATP [ 142 ] • DNA [ 10 ] • mtDNA [ 143 ] • Oxidized phospholipids [ 30 ] • Malondialdehyde [ 144 ] SAMPs • Annexin A1 [ 145 ] • Resolvin D1 [ 146 ] • Resolvin E1 [ 147 ] • Lipoxin A4 [ 148 ] • Prostaglandin-E2 [ 149 ] • Maresin [ 35 ] • Protectin [ 150 ] • Annexin A1 [ 151 ] • Resolvin D1 [ 85 ] • Resolvin E1 [ 85 ] • Resolvin D5 [ 85 ] • Lipoxin A4 [ 85 ] • Maresin 1 [ 85 ] • Resolvin E1 [ 152 ] HMGB1 high mobility group box 1, CIRP cold-inducible RNA-binding protein, EMAP II endothelial-monocyte-activating polypeptide II. DAMPs and SAMPs released in different cell death forms. • HMGB1 [ 10 ] • ATP [ 9 ] • DNA [ 9 ] • IL-1α [ 132 ] • IL-33 [ 120 ] • Histones [ 10 ] • RNA [ 9 ] • S100 proteins [ 133 ] • HSPs [ 134 ] • Uric acid [ 135 ] • mtDNA [ 136 ] • EMAP II [ 137 ] • Low molecular weight nucleotides [ 10 ] • HMGB1 [ 132 ] • ATP [ 10 ] • DNA [ 9 ] • IL-1α [ 132 ] • IL-33 [ 10 ] • Histones [ 10 ] • RNA [ 9 ] • S100A9 [ 10 ] • HSPs [ 9 ] • Uric acid [ 138 ] • mtDNA [ 10 ] • Long genomic DNA [ 138 ] • CIRP [ 9 ] • Cyclophilin A [ 139 ] • Spliceosome-associated Protein 130 [ 140 ] • HMGB1 [ 132 ] • ATP [ 9 ] • DNA [ 9 ] • IL-1α [ 132 ] • IL-1β [ 132 ] • IL-18 [ 132 ] • IL-33 [ 132 ] • mtDNA [ 132 ] • eCIRP [ 141 ] • ASC specks [ 10 ] • HMGB1 [ 9 ] • ATP [ 142 ] • DNA [ 10 ] • mtDNA [ 143 ] • Oxidized phospholipids [ 30 ] • Malondialdehyde [ 144 ] • Annexin A1 [ 145 ] • Resolvin D1 [ 146 ] • Resolvin E1 [ 147 ] • Lipoxin A4 [ 148 ] • Prostaglandin-E2 [ 149 ] • Maresin [ 35 ] • Protectin [ 150 ] • Annexin A1 [ 151 ] • Resolvin D1 [ 85 ] • Resolvin E1 [ 85 ] • Resolvin D5 [ 85 ] • Lipoxin A4 [ 85 ] • Maresin 1 [ 85 ] HMGB1 high mobility group box 1, CIRP cold-inducible RNA-binding protein, EMAP II endothelial-monocyte-activating polypeptide II. It is well known that when the intensity of apoptosis exceeds efferocytotic capacity, apoptosis turns into secondary necrosis. Similarly, early and late ferroptotic cells have been shown to differ in their ability to induce DC maturation in the co-culture assays [ 40 ]. Pyroptosis is a cellular response to the detection of DAMPs and PAMPs, so the release of DAMP following any cell death mode may induce pyroptosis as the second wave of cell death [ 41 ]. Apoptosis may follow necroptosis over time, for example in the cerebral ischemia-reperfusion stroke, which aggravates neuronal inflammation [ 42 ]. When cells suffer programmed necrosis, neighboring cells may become sensitive to necrotic cell death leading to synchronized regulated necrosis. These processes can simultaneously activate different programmed necrotic pathways in the affected tissue [ 43 ]. Dozens of articles also provide data that a blockage of a cell death route activates other death pathways, resulting in the desirous elimination of the cell, but occasionally inducing different immunological outcomes. For example, ferroptosis and necroptosis act in a coordinated manner: if the activity of one pathway decreases, that of the other improves to compensate it [ 42 ]. Symbolic molecules of cell death pathways have been described to regulate or initiate other cell death pathways. For example, caspase-3 and caspase-8 have been described as initiators of pyroptosis [ 22 ] and vice versa, caspase-1 was also indicated as the regulator of effector caspases [ 44 ]. While caspase-8 is a well-known inhibitor of necroptosis, caspase-9 has been published to be necessary for the death receptor and PRR-induced necroptosis [ 45 ]. Acetylated p53 and the pro-apoptotic Bid protein have been shown to contribute to ferroptosis [ 46 , 47 ]. Key molecules of necroptosis RIPK1, RIPK3 were indicated as apoptosis regulators and RIPK1, RIPK3 and MLKL are also involved in pyroptosis [ 48 ]. Expression of TAK1 [ 49 ], RIPK1 [ 50 ] and oxygen radicals [ 51 ] seems to affect all the mentioned cell death pathways, and ESCRT-III machinery can modify DAMP release in all of these necrotic cell death subroutines [ 52 ]. Molecular entanglement of cell death pathways may result in PANoptosis, bringing together the components of apoptosis necroptosis and pyroptosis into a complex [ 53 ]. This contemporaneous function of cell death pathways has been observed, especially after infections, but also in auto-inflammatory and metabolic disorders [ 54 ]. In addition, it is still unclear whether a particular type of cell death occurs through different signaling pathways, results in the same DAMP/SAMP production, or leads to different immune responses (Table 3 ). Table 3 Pros and cons of different forms of necroinflammation. Pros Cons Cell death modalities differ in the mechanism of DAMP release Each cell death process can be activated by multiple signaling pathways Different DAMPs are released during cell death modalities Timely different DAMPs can be released in the same cell death pathway Critical DAMPS of the Th differentiation, such as IL-1, IL-33, SAMPs seems to be produced dominantly upon specific cell death forms. Cell death pathways can work simultaneously Different posttranslational modifications of DAMPs are activated upon different cell death pathways Cell death processes can be sequential events, activating each other. Pros and cons of different forms of necroinflammation.

Usually, the late diagnosis of diseases makes it difficult to conclude whether the abnormal immune inflammation is the cause or result of an illness. Sterile inflammation can be the cause of many diseases, so its possible subtypes, their association with Th subpopulations, should be better elucidated. Characterization of the immunological outcome of cell death can determine the points of translational intervention in the regulation of many forms of sterile inflammation.

After intracellular, extracellular and parasitic infections, various cells and humoral factors specific to each type of immune response are activated. According to these pathogen groups, subtypes of the immune response can be classified, represented by groups of helper T cells (Th1, Th2, and Th17), cells that direct each immune arm principally by producing an appropriate cytokine panel. Regulatory T cells complete this picture as a general suppressor of the three kinds of the immune response. In the last decade, innate lymphoid cells (ILC) have been described as regulators of the immune response and classified into ILC1, ILC2, and ILC3 subtypes according to their differentiation and function. As part of innate immunity, these cells respond early to infections and regulate the immune response principally by their cytokine production. Tissue environmental factors, particularly the cytokine profile of sentinel immune cells, are critical in determining the polarization of Th and ILC cells. Th1/ILC1 differentiation of the immune response is initiated by the presence of type I and type II interferons, while IL-12 and IL-18 promote the production of interferon-γ (IFN-γ). Th2/ILC2 differentiation is mediated, among others, by IL-4, IL-13, IL-33; Th17/ILC3 by IL-1, IL-6, IL-23 and peripheral Tregs by TGFβ and IL-2 production [ 8 ]. As stimulant factors, these cytokine motifs determine the direction of the immune response and the types of inflammation (Fig. 1 ). Fig. 1 Sterile inflammation in parallel with pathogen-induced immune response. Distinct classes of pathogens induce different immune responses, commonly known as type 1, 2, and 3 immunity, resulting in the activation of different T helper cell subsets. While pathogen-induced immune responses can be classified into different subclasses, called type 1, 2, and 3 inflammation, DAMP-induced necroinflammation is not yet linked to this partitioning system. Necroinflammation can be classified as an independent type of inflammation that can be well distinguished from the other three major classes, or necroinflammation may also have subtypes. If it can be divided into subtypes, these subtypes can be compatible with subclasses of pathogen-induced processes, or can be different from them, inducing unique types of immune reactions. Distinct classes of pathogens induce different immune responses, commonly known as type 1, 2, and 3 immunity, resulting in the activation of different T helper cell subsets. While pathogen-induced immune responses can be classified into different subclasses, called type 1, 2, and 3 inflammation, DAMP-induced necroinflammation is not yet linked to this partitioning system. Necroinflammation can be classified as an independent type of inflammation that can be well distinguished from the other three major classes, or necroinflammation may also have subtypes. If it can be divided into subtypes, these subtypes can be compatible with subclasses of pathogen-induced processes, or can be different from them, inducing unique types of immune reactions.

The response of sentinel immune cells, primarily macrophages, dendritic cells and mast cells, initiates the processes leading to the classical signs of inflammation. The pattern recognition receptors (PRRs) of the initiator cells are activated by pathogen-associated molecular patterns (PAMPs), and also by damage-associated molecular patterns (DAMPs). Sterile inflammation in the absence of pathogens can be induced by DAMPs released from the cells or formed in the interstitial space. The most common mechanism of sterile inflammation is necroinflammation, where DAMP production associated with dysregulated cell death is the cause of the process [ 1 ]. However, at the same time, during cell death, various suppressing/inhibiting DAMPs (SAMPs, iDAMPs, or also termed special pro-resolving mediators SPMs) could be released, including molecules such as prostaglandin E2 [ 2 ] (PGE2), resolvins, protectins or maresins, and lipoxins [ 3 ] that contribute to inflammation-resolving pathways [ 4 ]. Sterile inflammation, especially in its chronic form, could be the cause of many different diseases, including but not limited to various forms of neurodegenerative disorders, skin- and intestinal tract-related diseases, obesity, atherosclerosis, hepatitis, pancreatitis and also chronic low-grade inflammation in the elderly [ 5 ] (Table 1 ). However, the exact cause and mechanism of the cell death process in most inflammatory diseases is not yet clear. Table 1 Examples of inflammatory diseases in which apoptosis, necroptosis, pyroptosis or ferroptosis are involved. Tissue/cell death Apoptosis Necroptosis Pyroptosis Ferroptosis Neurodegenerative disorders Alzheimer's disease, Parkinson's disease [ 108 , 109 ], Huntington's disease [ 109 ] Multiple sclerosis , Alzheimer’s disease, amyotrophic lateral sclerosis [ 14 ] Multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease [ 110 ] Alzheimer's disease, Parkinson's disease, Huntington's disease [ 31 ] Metabolic disorders Obesity, insulin resistance, type-2 diabetes [ 111 ] Crohn’s disease, inflammatory bowel disease [ 14 ] Type 1–2 diabetes, inflammatory bowel disease [ 112 ] Diabetes mellitus [ 113 ] Liver diseases Nonalcoholic steatohepatitis cirrhosis [ 111 ] Alcoholic liver disease, nonalcoholic fatty liver disease [ 14 ] Alcoholic hepatitis, nonalcoholic fatty liver disease [ 112 ] Nonalcoholic fatty liver and alcoholic liver diseases, hemochromatosis, drug-induced liver injury [ 114 ] Autoimmune diseases Systemic lupus erythematosus, rheumatoid arthritis [ 109 ] Rheumatoid arthritis, autoimmune arthritis [ 115 ] Sjogren's syndrome, rheumatoid arthritis, systemic lupus erythematosus [ 112 ] Systemic lupus erythematosus [ 116 ] Cardiovascular diseases Atherosclerosis, cardiovascular diseases [ 108 , 109 ] Chronic heart failure [ 14 ] Atherosclerosis, ischemic heart disease, myocardial infarction [ 111 , 117 ] Atherosclerosis [ 114 ] Skin diseases Systemic lupus erythematosus [ 108 ] Lichen planus, systemic lupus erythematosus [ 14 ], psoriasis [ 115 ] Psoriasis [ 118 ] Keratinocyte death [ 119 ] Pulmonary diseases Chronic obstructive pulmonary disease [ 108 ] acute respiratory distress syndrome [ 120 ] Chronic obstructive pulmonary disease [ 115 ] Acute lung injury [ 111 ] Chronic obstructive pulmonary disease [ 113 ] Dental disorders ND Periodontitis [ 14 ] Gingivitis [ 121 ] ND Cancer Breast carcinoma, colorectal cancer and many other tumors [ 122 ] Pancreatic cancer [ 14 ] breast cancer [ 123 – 125 ] Liver, gastric tissues, uterine, cervical and breast cancers [ 111 ], melanoma,lung cancer, colorectal cancer [ 126 ] Hepatocellular carcinoma [ 114 ] Disorders in the reproductive tract Preeclampsia [ 127 ] Reproductive senescence, early menopause [ 128 ] Preeclampsia, preterm birth [ 111 ], endometriosis, infertility, reproductive senescence [ 129 ] Preeclampsia [ 130 ] Kidneys Nephropathy, acute kidney injury [ 131 ] Acute kidney injury, autosomal dominant polycystic kidney disease [ 14 ] Acute kidney injury [ 113 ] Inflammation and tissue injury in kidney [ 31 ] acute kidney injury [ 115 ] Examples of inflammatory diseases in which apoptosis, necroptosis, pyroptosis or ferroptosis are involved. Over the past few years, new cell death processes have been described and classified as regulated cell death modalities that can be characterized by well-defined, unique, tightly regulated signaling pathways [ 6 ]. These cell death processes differ in the morphology and enzyme activity of dying cells, and their impact on the outcome of innate and adaptive responses. Most of these regulated cell death mechanisms have been classified as necrotic, proinflammatory cell death stimulating innate immune reactions. Activation of adaptive immunity, especially cytotoxic T cells by immunogenic cell death has also been described [ 7 ]. However, the interaction between different inflammatory cell death processes, necroptosis, pyroptosis, and ferroptosis with different types of helper T cells has not been studied. The main characteristic profile of infections, i.e. the presence of intracellular, extracellular or parasitic pathogens, determines the three main types of immune responses that are supervised by Th1, Th17, Th2 cells. These branches of the immune response differ functionally and also in the composition of reactive cells. As well as the costimulatory molecule profile and cytokine milieu, the presence and proportion of DAMPs and SAMPs may be critical in the polarization of the T cell response. We attempted to identify a link between the different cell death pathways and their effect on the polarisation of the immune response. In this review, we study the immunological outcome of necroinflammatory cell death pathways one by one. We compare molecules released during apoptosis, necroptosis, pyroptosis, ferroptosis, and determine immunological decision-making on how these cell death pathways regulate Th1, Th2, Th17, and regulator T cell-directed immune responses through secreted DAMP and SAMP profiles.

The polarization of naïve and effector T cells is also strongly influenced by the soluble mediators appearing in their microenvironment. Different DAMPs, SAMPs and cytokines are produced during each cell death modality. In this section, we have collected how different cell death pathways may affect helper T cell and ILC polarization, which determines the type of inflammation (Fig. 3 ). Fig. 3 DAMP and SAMP molecules regulating Th cell differentiation. Types of cell death, DAMP and SAMP molecules directly associated with T helper cell subpopulations based on literature data. HMGB1 High mobility group box 1, PGE2 Prostaglandin E 2 , TGFβ Transforming growth factor-beta. Types of cell death, DAMP and SAMP molecules directly associated with T helper cell subpopulations based on literature data. HMGB1 High mobility group box 1, PGE2 Prostaglandin E 2 , TGFβ Transforming growth factor-beta. High levels of TLR4 in necrotizing enterocolitis (NEC) activate necroptosis of intestinal epithelial cells, contributing to local inflammation that may have been prevented by the use of Necrostatin-1, a necroptosis inhibitor [ 95 ]. Significant increases in the level of IL-6, IL-17 and TNFalpha have been mentioned in NEC, confirming the role of cell death in Th1-and Th17-related inflammation. In hyperinflammatory tumors, the microenvironment is generally rich in iron, which, by inducing oxidative stress and cell death on T cells and B cells, contributes to the progression of cancer. Iron chelating agents can be used to treat the iron overload, which has been demonstrated to increase the Th1 response [ 96 , 97 ]. Thus, induction of ferroptosis in immune-excluded tumors may provide all the benefits of “immunogenic cell death” without the disadvantages of immunosuppression. Cadmium toxic pollutant reduces the production of IFNγ and increases the levels of IL-4, IL-6 and IL-10, thereby weakening the Th1 response but enhancing the activity of Th2 cells [ 98 ]. Cadmium induces necroptosis with increased expression of RIPK1, RIPK3 and MLKL and cadmium-induced inflammation is inhibited by necrostatin-1 in a porcine model. Further enhancing the effect of necroptosis on Th2 polarization, ILC2s have been shown to produce IL-4 prior to any other cell types following doxorubicin (DOX)-induced myocardial necroptosis [ 99 ]. Necroptosis may also support the effector activity of Th17 cells following recognition of fungi. A special case of this is when necroptosis of macrophages in a process called metaphorosis can lead to calcineurin-dependent lateral transfer of A. fumigates to live macrophages to downregulate fungal germination [ 100 , 101 ]. Selenium deficiency induced accelerated cell necroptosis in IPEC-J2 cells, resulting in increased expression of IL-1β, IL-6, IL-7 and IL-17, while the expression of IFNγ, IL-10 and IL-4 is down-regulated indicating a Th17 polarization of helper T cells [ 100 ]. Intestinal epithelial cell necroptosis, which results in the recruitment and activation of ILC3s and IL-22 production, also enhances Th17 responses [ 102 ]. IL-18 released by pyroptotic cells is involved in promoting the IL-17 production of Th17 cells in osteoporosis. In this process, pyroptotic activation of NLRP3 contributes to bone damage also through activation of T lymphocytes [ 103 ]. In the intestinal lamina propria, in the presence of commensal microbes and dietary antigens, a sensitive, highly plastic balance of Th17 and Treg cells is established. The uptake of apoptotic cells by DCs induces their IL-6 and TGFβ production, leading to the differentiation of Th17 cells from naïve CD4 + lymphocytes [ 104 ]. However, in this microenvironment, the presence of microbes in apoptotic cells is highly likely, and accordingly TLR2 activation precedes the production of Th17 cytokines. Apoptotic cells are easily recognized and absorbed by phagocytes, leading to their anti-inflammatory activity. In this process efferocytes secrete anti-inflammatory cytokines, like IL-10 and TGFβ, but less of inflammatory cytokines such as TNFα, IL-1β and IL-12. The presence of apoptotic cells induces the differentiation of naïve T cells into Treg cells, and also suppresses the activity of effector T lymphocytes [ 105 ]. In addition, the uptake of apoptotic cells results in a decrease in MHC-II expression on the surface of professional antigen-presenting cells (APCs). Modification of MHC and co-stimulatory/inhibitory receptor expressions presumably plays a critical role in Th17 and Treg induction during DC-T cell interaction [ 106 ]. However, APC types can elicit different responses to apoptotic cells. Macrophages can induce mainly tolerogenic, while DCs can induce immunogenic responses. Uptake of apoptotic cells by phagocytes not only induces regulatory T cell differentiation, but also inhibits polarization of other T helper subtypes by inhibiting the production of IL-12, IFNγ, and Th17 cell-derived cytokines, IL-17 and IL-23 [ 107 ].

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