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Stimulator of interferon genes (STING) contributes to immune responses against tumors and may control viral infection including SARS-CoV-2 infection. However, activation of the STING pathway by airway silica or smoke exposure leads to cell death, self-dsDNA release, and STING/type I IFN dependent acute lung inflammation/ARDS. The inflammatory response induced by a synthetic non-nucleotide-based diABZI STING agonist, in comparison to the natural cyclic dinucleotide cGAMP, is unknown. A low dose of diABZI (1 µg by endotracheal route for 3 consecutive days) triggered an acute neutrophilic inflammation, disruption of the respiratory barrier, DNA release with NET formation, PANoptosis cell death, and inflammatory cytokines with type I IFN dependent acute lung inflammation. Downstream upregulation of DNA sensors including cGAS, DDX41, IFI204, as well as NLRP3 and AIM2 inflammasomes, suggested a secondary inflammatory response to dsDNA as a danger signal. DNase I treatment, inhibition of NET formation together with an investigation in gene-deficient mice highlighted extracellular DNA and TLR9, but not cGAS, as central to diABZI-induced neutrophilic response. Therefore, activation of acute cell death with DNA release may lead to ARDS which may be modeled by diABZI. These results show that airway targeting by STING activator as a therapeutic strategy for infection may enhance lung inflammation with severe ARDS. STING agonist diABZI induces neutrophilic lung inflammation and PANoptosis A , Airway STING priming induce a neutrophilic lung inflammation with epithelial barrier damage, double-stranded DNA release in the bronchoalvelolar space, cell death, NETosis and type I interferon release. B , 1. The diamidobenzimidazole (diABZI), a STING agonist is internalized into the cytoplasm through unknown receptor and induce the activation and dimerization of STING followed by TBK1/IRF3 phosporylation leading to type I IFN response. STING activation also leads to NF-kB activation and the production of pro-inflammatory cytokines TNFα and IL-6. 2. The activation of TNFR1 and IFNAR1 signaling pathway results in ZBP1 and RIPK3/ASC/CASP8 activation leading to MLKL phosphorylation and necroptosis induction. 3. This can also leads to Caspase-3 cleavage and apoptosis induction. 4. Self-dsDNA or mtDNA sensing by NLRP3 or AIM2 induces inflammsome formation leading to Gasdermin D cleavage enabling Gasdermin D pore formation and the release mature IL-1β and pyroptosis. NLRP3 inflammasome formation can be enhanced by the ZBP1/RIPK3/CASP8 complex. 5. A second signal of STING activation with diABZI induces cell death and the release of self-DNA which is sensed by cGAS and form 2′3′-cGAMP leading to STING hyper activation, the amplification of TBK1/IRF3 and NF-kB pathway and the subsequent production of IFN-I and inflammatory TNFα and IL-6. This also leads to IFI204 and DDX41 upregulation thus, amplifying the inflammatory loop. The upregulation of apoptosis, pyroptosis and necroptosis is indicative of STING-dependent PANoptosis.

Liver fibrosis is a consequence of chronic liver disease, causing morbidity and mortality. Interleukin-33 (IL-33) is a critical mediator of inflammation, which may be involved in the development of liver fibrosis. Here, we investigated the role of IL-33 in human patients and experimental bile-duct ligation (BDL)-induced fibrosis in mice. We report increased hepatic IL-33 expression in the murine BDL model of fibrosis and in surgical samples obtained from patients with liver fibrosis. Liver injury, inflammatory cell infiltration and fibrosis were reduced in the absence of the IL-33/ST2 receptor, and the activation of hepatic stellate cells (HSCs) was decreased in ST2-deficient mice. Recombinant IL-33 activated HSCs isolated from C57BL/6 mice, leading to the expression of IL-6, TGF-β, α-SMA and collagen, which was abrogated in the absence of ST2 or by pharmacological inhibition of MAPK signaling. Finally, administration of recombinant IL-33 significantly increased hepatic inflammation in sham-operated BL6 mice but did not enhance BDL-induced hepatic inflammation and fibrosis. In conclusion, BDL-induced liver inflammation and fibrosis are dependent on ST2 signaling in HSCs, and therefore, the IL-33/ST2 pathway may be a potential therapeutic target in human patients with chronic hepatitis and liver fibrosis.

Systemic inflammatory response syndrome (SIRS) can be primed by infectious or non-infectious stimuli and may progress to life-threatening organ failure. An altered balance between pro- and anti-inflammatory response is commonly observed in SIRS, yet the core molecular events driving severe SIRS remain poorly defined. Moreover, the roles of macrophages and autophagy in SIRS have been pointed out. Here a high susceptibility to LPS-induced lethal shock in mice deficient in autophagy in myeloid cells ( Atg5 f/f LysM-cre + ) following a single dose of 0.5 mg/kg (60% mortality vs. 0% in wild type after 24h) was observed. Using a very low dose of LPS (0.1 mg/kg), Atg5 f/f LysM-cre + mice showed rapid tissue injury, notably in the liver and spleen, accompanied by an altered macrophage phenotype. Macrophages in the spleen and the liver appeared swollen and showed a loss of cellular content, including iron. In contrast, hepatocytes in Atg5 f/f LysM-cre + mice accumulated more iron, which was associated with elevated reactive oxygen species levels compared to wild-type mice. Notably, the livers of LPS-treated Atg5 f/f LysM-cre + mice exhibited increased ferroptotic and apoptotic cell death and extensive pyroptosis in both the spleen and liver. Flow cytometric analysis, immunofluorescence, and RNA sequencing supported the marked pro-inflammatory phenotype of macrophages in LPS-treated Atg5 f/f LysM-cre + mice. In conclusion, during LPS-induced inflammation, autophagy deficiency in myeloid cells profoundly alters macrophage phenotype, disrupts iron trafficking, and promotes tissue injury through multiple forms of cell death.

Airborne ozone exposure causes severe lung injury and inflammation. The aryl hydrocarbon Receptor (AhR) (1), activated in pollutant-induced inflammation, is critical for cytokine production, especially IL-22 and IL-17A. The role of AhR in ozone-induced lung inflammation is unknown. We report here that chronic ozone exposure activates AhR with increased tryptophan and lipoxin A4 production in mice. AhR mice show increased lung inflammation, airway hyperresponsiveness, and tissue remodeling with an increased recruitment of IL-17A and IL-22-expressing cells in comparison to control mice. IL-17A- and IL-22-neutralizing antibodies attenuate lung inflammation in AhR and control mice. Enhanced lung inflammation and recruitment of ILC3, ILC2, and T cells were observed after T cell-specific AhR depletion using the AhR -deficient mice. Together, the data demonstrate that ozone exposure activates AhR, which controls lung inflammation, airway hyperresponsiveness, and tissue remodeling via the reduction of IL-22 expression.

Atopic dermatitis (AD) is a chronic Th2 type inflammatory skin disorder. Here we report that MyD88 signaling is crucial in the pathogenesis of experimental AD induced by vitamin D3 analog MC903. The clinical signs and inflammation caused by MC903 are drastically reduced in MyD88 −/− mice with diminished eosinophil, neutrophil infiltration and Th2 cytokine expression. The biological effect of interleukin-1 (IL-1) family members relies on MyD88 signaling. We observed a strong upregulation of IL-1 family cytokine expression, including IL-1 α , IL-1 β , IL-33, IL-18, IL-36 α , IL-36 β , IL-36 γ and IL-36Ra. Therefore, we asked which cytokine of the IL-1 family would be essential for MC903-induced AD syndrome. We find a significant reduction of AD in IL-33 −/− and IL-33R/ST2 −/− mice, only a minor reduction in double IL-1 αβ −/− mice and no difference in IL-36R −/− and IL-36Ra −/− mice. IL-33 is expressed in keratinocytes, and MyD88 signaling in dendritic cells (DCs) is crucial for AD development as inflammation was drastically reduced in DC-specific MyD88 −/− mice (CD11c-cre × MyD88-floxed). Taken together, the data demonstrate a critical role of MyD88 in DCs and of IL-33 signaling via ST2 in MC903-induced AD. These data suggest that IL-33/IL-33R may be a therapeutic target of AD.

Cerebral malaria (CM) is associated with a high mortality rate and long-term neurocognitive impairment in survivors. The murine model of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA)-infection reproduces several of these features. We reported recently increased levels of IL-33 protein in brain undergoing ECM and the involvement of IL-33/ST2 pathway in ECM development. Here we show that PbA-infection induced early short term and spatial memory defects, prior to blood brain barrier (BBB) disruption, in wild-type mice, while ST2-deficient mice did not develop cognitive defects. PbA-induced neuroinflammation was reduced in ST2-deficient mice with low Ifng, Tnfa, Il1b, Il6, CXCL9, CXCL10 and Cd8a expression, associated with an absence of neurogenesis defects in hippocampus. PbA-infection triggered a dramatic increase of IL-33 expression by oligodendrocytes, through ST2 pathway. In vitro, IL-33/ST2 pathway induced microglia expression of IL-1β which in turn stimulated IL-33 expression by oligodendrocytes. These results highlight the IL-33/ST2 pathway ability to orchestrate microglia and oligodendrocytes responses at an early stage of PbA-infection, with an amplification loop between IL-1β and IL-33, responsible for an exacerbated neuroinflammation context and associated neurological and cognitive defects.

Idiopathic pulmonary fibrosis is a progressive, devastating, and yet untreatable fibrotic disease of unknown origin. Interleukin-33 (IL-33), an IL-1 family member acts as an alarmin with pro-inflammatory properties when released after stress or cell death. Here, we investigated the role of IL-33 in the bleomycin (BLM)-induced inflammation and fibrosis model using mice IL-33 receptor [chain suppression of tumorigenicity 2 (ST2)] mice compared with C57BL/6 wild-type mice. Unexpectedly, 24 h post-BLM treatment ST2-deficient mice displayed augmented inflammatory cell recruitment, in particular by neutrophils, together with enhanced levels of chemokines and remodeling factors in the bronchoalveolar space and/or the lungs. At 11 days, lung remodeling and fibrosis were decreased with reduced M2 macrophages in the lung associated with M2-like cytokine profile in ST2-deficient mice, while lung cellular inflammation was decreased but with fluid retention (edema) increased. magnetic resonance imaging (MRI) analysis demonstrates a rapid development of edema detectable at day 7, which was increased in the absence of ST2. Our results demonstrate that acute neutrophilic pulmonary inflammation leads to the development of an IL-33/ST2-dependent lung fibrosis associated with the production of M2-like polarization. In addition, non-invasive MRI revealed enhanced inflammation with lung edema during the development of pulmonary inflammation and fibrosis in absence of ST2.

Air pollution associated with ozone exposure represents a major inducer of respiratory disease in man. In mice, a single ozone exposure causes lung injury with disruption of the respiratory barrier and inflammation. We investigated the role of interleukin-1 (IL-1)-associated cytokines upon a single ozone exposure (1 ppm for 1 h) using IL-1α-, IL-1β-, and IL-18-deficient mice or an anti-IL-1α neutralizing antibody underlying the rapid epithelial cell death. Here, we demonstrate the release of the alarmin IL-1α after ozone exposure and that the acute respiratory barrier injury and inflammation and airway hyperreactivity are IL-1α-dependent. IL-1α signaling IL-1R1 depends on the adaptor protein myeloid differentiation factor-88 (MyD88). Importantly, epithelial cell signaling is critical, since deletion of MyD88 in lung type I alveolar epithelial cells reduced ozone-induced inflammation. In addition, intratracheal injection of recombinant rmIL-1α in MyD88 mice led to reduction of inflammation in comparison with wild type mice treated with rmIL-1α. Therefore, a major part of inflammation is mediated by IL-1α signaling in epithelial cells. In conclusion, the alarmin IL-1α released upon ozone-induced tissue damage and inflammation is mediated by MyD88 signaling in epithelial cells. Therefore, IL-1α may represent a therapeutic target to attenuate ozone-induced lung inflammation and hyperreactivity.

Tumor Necrosis Factor (TNF) is a pleiotropic cytokine consisting of soluble and transmembrane forms, with distinct roles in inflammation and immunity. TNF is an important factor in allergic airway inflammation. However, the disparate functions of soluble (sol) and transmembrane (tm) TNF in lung pathology are not well understood. Our aim was to assess the activities of solTNF and tmTNF in murine models of allergic airway disease, and to evaluate the efficacy of solTNF-selective inhibition. We used ovalbumin sensitization and challenge of TNF knockout, tmTNF knockin, and wild-type C57BL/6 mice to distinguish differences in airway inflammation and hyperreactivity mediated by solTNF and tmTNF. Functions of solTNF and tmTNF in hyperresponsive, wild-type Balb/c mice were assessed by comparing dominant-negative anti-TNF biologics, which antagonize solTNF yet spare tmTNF, to etanercept, a nonselective inhibitor of both TNF forms. Responses in transgenic C57BL/6 mice demonstrated that solTNF, and not tmTNF, is necessary to drive airway inflammation. In Balb/c mice, dominant-negative TNF biologics administered during immunization decreased the recruitment of eosinophils and lymphocytes into the bronchoalveolar space and lung parenchyma, reduced specific serum IgE, goblet-cell hyperplasia, and eosinophilic inflammation, and suppressed methacholine-induced airway hyperreactivity. Concentrations of IL-5, CCL5/RANTES, CCL11/eotaxin, and CCL17/TARC were also reduced in bronchoalveolar lavage. Dominant-negative TNFs reduced lung eosinophilia, even when given only during antigen challenge. The selective inhibition of soluble TNF suppresses inflammation, hyperreactivity, and remodeling in transgenic and wild-type murine models of allergic airway disease, and may offer safety advantages in therapies that preserve the immunoprotective functions of transmembrane TNF.