Why are interferons important

Activation of the inflammasome is a key event in inflammatory immune response. The inflammasomes are cytosolic multiprotein complexes that are composed of an inflammasome-initiating sensor, apoptosis-associated speck-like protein containing a CARD ASC acts as an adaptor protein and the protease-caspase In addition, inflammasomes initiate pyroptotic cell death 52 , 57 , Pyroptosis involves cell swelling, membrane rupture, and release of the cytoplasmic content into the extracellular space 58 — Recently, several excellent reviews described mechanism of inflammasome activation 52 , 56 , 64 , Several NLR family members have been described as components of inflammasomes: Nlrp1b inflammasome 66 , 67 , Naip-Nlrc4 inflammasome 68 , 69 , the Nlrp6 inflammasome 70 , the Nlrp12 inflammasome, the Aim2 inflammasome 28 , 71 , the RIG-I inflammasome 72 , and the IFI16 inflammasome Particularly, the activation of Nlrp3 inflamamsome is well characterized 55 , 64 , 74 , Since it responds to variety of stimuli, many different mechanisms of its activation have been proposed, including the release of oxidized mitochondrial DNA, production of reactive oxygen species and mitochondrial dysfunction, lysosomal destabilization, changes in intracellular calcium levels, the formation of large non-specific membrane.

Moreover, Nlrp3 activation can be regulated through direct posttranslational modifications, such as ubiquitination Recently, several independent studies reported non-canonical inflammasome activation 78 — While canonical inflammasome activation results in caspase-1 cleavage and activation, the activation of a non-canonical inflammasome results in activation of procaspase The mouse caspase has high similarities to caspase-1 and is orthologous to human caspases-4 and -5 81 , Only caspasedeficient mice, but not caspasedeficient mice were partially protected from septic death 78 , Recent reports showed that caspase was involved in the response to cytosolic LPS, independently of TLR4 and was integral to the pathology of LPS-mediated endotoxic shock in mice Moreover, it was shown that human caspase-4 and caspase-5 and mouse caspase bound directly to LPS in the cytosol With the difference to canonical inflammasome activation were the receptor Nlrp3 and ASC form a scaffold on which caspase-1 can oligomerize, in non-canonical infalmmasome activation, caspase oligomerization occurs directly upon binding to LPS It was reported that canonical Nlrp3 inflammasome activation downstream of caspase-4 and caspase activation was dependent on potassium efflux 90 — Yang et al.

Inhibition of inflammasome activation by decoy proteins uses proteins structurally related to components of inflammasome and competing for the same adaptors. The CARD-only proteins and PYD-only proteins POPs function as endogenous dominant negative proteins that modulate the activity of inflammasomes and protect from excessive inflammation 94 , The genes encoding these decoy proteins, POPs, are located on the same chromosome, in the proximity of genes that encode their ligands: the gene encoding POP1 is located on human chromosome 16 next to the gene encoding ASC Interferons could contribute to inflammasome activation through several different mechanisms Figure 1.

It was reported that type I IFNs are required for the caspase expression, which contributes to activation of non-canonical inflammasome Several recent studies have shown that IFN-inducible endogenous proteins could act also as negative regulators and thus inhibit inflammasome activation 97 , Among others, interferon-inducible GBPs not only mediate host resistance to pathogens but also promote inflammasome activation in bacterial infections , Not only POPs but also metabolites like hydroxycholesterol, an oxysterol and is derived from cholesterol, suppress inflammasome activation Work of Reboldi et al.

The authors proposed that hydroxycholesterol antagonized the sterol response element-binding protein processing Moreover, cholesterol hydroxylase-deficient mice showed increased sensitivity to LPS-induced septic shock Figure 1. Type I interferons IFNs and inflammasome activation. Active caspase-1 and caspase cleave GSDMD and the released gasdermin-N domain binds to phosphoinositides in the plasma membrane, oligomerizes to generate membrane pores, and initiates cell death-pyroptosis.

NO plays an important role in a defense against pathogens, it could be oxidized to reactive nitrogen oxide species, that S -nitrosate thiols in proteins 15 , Mishra et al. Also study by Mao et al. Guarda et al. In addition, they demonstrated that the recruitment of inflammatory cells neutrophils and monocytes into peritoneal cavity was significantly lower in poly I:C pretreated mice, than in control animals injected only with LPS.

Several recent studies reported cross talk between IFNs and inflammasome activation in bacterial infections 79 , , , , Rathinam et al. Gurung et al. Aachoui et al. Oficjalska et al. GBPs have also been shown to regulate the entry of LPS into the cytosol by, as yet, poorly defined mechanisms However, studies on different mouse strain of GBP5 - deficient mice could not confirm the initial results , Despite the uncertainty surrounding the role of GBP5 in Nlrp3 inflammasome activation, studies using mice lacking the entire cluster of GBP genes on chromosome 3, have firmly confirmed a functional link between GBPs and the activation of the canonical NLRP3 and AIM2 inflammasomes, as well as the non-canonical caspase inflammasomes.

Figure 2. ZBP1-deficient mice were protected from mortality during IAV infection, due to reduced inflammatory response I have summarized considerable, but by no means all evidence documenting the role of IFNs in inflammasome activation and inflammation. Several recent studies reported the essential role of type I IFNs in non-canonical Nlrp3 inflammasome activation and pyroptosis.

Different levels of regulation are involved in the cross talk of IFNs in inflammasome. Dysregulated type I-IFN production could lead to a cell death. However, a recent study reported that in the absence of active proapoptotic caspases-3 and -7, mitochondrial outer membrane permeabilization by Bax and Bak resulted in the expression of type I-IFNs. Particularly, the role of STAT and other protein modification in IFN signaling pathways could give us important insight into the regulatory mechanisms.

IFN-induced GBPs were reported to have an important role in caspase activation and pyroptotic cell death. How does the polymorphisms of GBPs influence inflammasome activation and inflammation is yet to be determined.

Future research should explore the detailed molecular mechanisms that are responsible for type I IFN-dependent cell death and inflammasome activation in inflammatory response. Moreover, recently, several studies determined the role of cytokines in metabolic reprograming and inflammasome activation The role cross talk of IFNs, inflammasomes, and metabolism could be a future frontier for the cutting edge research.

Identification of the factors involved in inflammasome regulation and signaling will lead to the identification of novel targets for therapeutic intervention. The author confirms being the sole contributor of this work and approved it for publication. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author acknowledges the financial support from the Slovenian Research Agency research core funding No.

Medzhitov R. Inflammation new adventures of an old flame. Cell —6. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol — Origin and physiological roles of inflammation. Nature — Pathogen recognition and innate immunity. Cellular responses to interferon-g. The effects of nebulized recombinant interferon-gamma in asthmatic airways.

J Allergy Clin Immunol 95 : A direct role for IFN-g in regulation of Th1 cell development. J Immunol : T helper 1 cells and interferon gamma regulate allergic airway inflammation and mucus production.

Constant SL, Bottomly K Mice lacking the IFN-g receptor have impaired ability to resolve a lung eosinophilic inflammatory response associated with a prolonged capacity of T cells to exhibit a Th2 cytokine profile. Science : Macrophages induce cellular immunity by activating Th1 cell responses and suppressing Th2 cell responses. Systemic and local interferon gamma gene delivery to the lungs for treatment of allergen-induced airway hyperresponsiveness in mice.

Hum Gene Ther 10 : Nitric oxide inhibits IgE-mediated degranulation of mast cells and is the principal intermediate in IFN-g-induced suppression of exocytosis.

Immunity 17 : The molecular cell biology of interferon-g and its receptor. Annu Rev Immunol 11 : Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Cell Immunol : IFN-g production by antigen-presenting cells: mechanisms emerge. Trends Immunol 22 : Anti-proliferative effect of IFN-g in immune regulation I. Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process. Immunity 2 : Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma.

J Clin Invest 87 : Allergen-specific Th1 cells fail to counterbalance Th2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest : Inhalation of nitric oxide modulates adult human bronchial tone. Am Rev Respir Dis : Huang H, Paul WE Impaired interleukin 4 signaling in T helper type 1 cells. Interferon-induces tyrosine phosphorylation of interferon-g receptor and regulated association of protein kinases, JAK1 and JAK2, with its receptor.

J Biol Chem : Clin Exp Immunol : Sustained T-bet expression confers polarized human Th2 cells with Th1-like cytokine production and migratory capacities. J Allergy Clin Immunol : Allergen-induced cytokine production in atopic disease and its relationship to disease severity. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Scand J Immunol 51 : Hlx is induced by and genetically interacts with T-bet to promote heritable Th1 gene induction.

Signaling and transcription in T helper development. Annu Rev Immunol 18 : Gene expression of the GATA-3 transcription factor is increased in atopic asthma. Reduced interferon-gamma but normal IL-4 and IL-5 release by peripheral blood mononuclear cells from Xhosa children with atopic asthma.

Constitutive expression of type I NOS in human airway smooth muscle cells: evidence for an antiproliferative role. Lack of interferon-g receptor b chain and the prevention of interferon g signaling in Th1 cells. Trends Immunol 23 : Interferon g is required for activation-induced death of T lymphocytes.

By highlighting the current state-of-knowledge of the two archetypical mucosal surfaces e. We then discuss in detail the role of each IFN in controlling pathogen infections in intestinal and respiratory epithelial cells.

Certain symptoms of infections, such as fever, muscle pain and "flu-like symptoms", are also caused by the production of IFNs and other cytokines. More than twenty distinct IFN genes and proteins have been identified in animals, including humans. IFNs belonging to all three classes are important for fighting viral infections and for the regulation of the immune system. It is produced in activated T-cells and natural killer cells.

However, this cytokine potentiates the effects of the type I IFNs. It also stimulates macrophages to kill bacteria that have been engulfed. However, the evidence of its in vivo bioactivity is still debatable. All interferons share several common effects: they are antiviral agents and they modulate functions of the immune system.

Administration of Type I IFN has been shown experimentally to inhibit tumor growth in animals, but the beneficial action in human tumors has not been widely documented.

A virus-infected cell releases viral particles that can infect nearby cells. However, the infected cell can prepare neighboring cells against a potential infection by the virus by releasing interferons.

In response to interferon, cells produce large amounts of an enzyme known as protein kinase R PKR. This enzyme phosphorylates a protein known as eIF-2 in response to new viral infections; the phosphorylated eIF-2 forms an inactive complex with another protein, called eIF2B, to reduce protein synthesis within the cell. Another cellular enzyme, RNAse L—also induced by interferon action—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes.

Inhibited protein synthesis destroys both the virus and infected host cells.