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Recently, we established a doxycycline‐inducible human tumor necrosis factor alpha (TNFα)‐transgenic mouse line, ihTNFtg. Non‐induced young and elderly mice showed low but constitutive expression of hTNFα due to promoter leakiness. The persistently present hTNFα stimulated endogenous pro‐inflammatory mouse mS100A8/A9 alarmins. Secreted mS100A8/A9 in turn induced the expression and release of mouse mTNFα. The continuous upregulation of pro‐inflammatory mTNFα and mS100A8/A9 proteins, due to their mutual expression dependency, gradually led to increased levels in colon tissue and blood. This finally exceeded the threshold levels tolerated by the healthy organism, leading to the onset of intestinal inflammation. Here, recombinant hTNFα functioned as an initial trigger for the development of chronic inflammation. Crossing ihTNFtg mice with S100A9KO mice lacking active S100A8/A9 alarmins or with Rag1KO mice lacking T and B lymphocytes completely abrogated the development of colonic inflammation, despite the still leaky hTNFα promoter. Furthermore, both the intensity of the immune response and the strength of immunosuppressive Treg induction was found to depend on the major histocompatibility complex (MHC) genetic composition. In summary, the onset of intestinal inflammation in elderly mice depends on at least four factors that have to be present simultaneously: TNFα upregulation, S100A8/A9 protein expression, functional T lymphocytes and genetic composition, with the MHC haplotype being of central importance. Only joint action of these factors leads to chronic intestinal inflammation, while absence of any of these determinants abrogates the development of the autoimmune disorder. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

MK2 and MK3 are downstream targets of p38 and ERK1/2. They control the mRNA stability of several inflammatory cytokines, including TNF-α and IL-10. Whereas MK2 is expressed ubiquitously, the expression of MK3 is restricted to muscle, liver, and heart tissues and T and NK cells. Using Aft-deficient and wild-type (WT) mice, we demonstrated an inhibitory effect of MK3, but not of MK2, on interferon (IFN)-γ expression in T and NK lymphocytes. The results provided evidence that the inhibitory effect of MK3 is based on negative feedback phosphorylation of p38 and ERK1/2, which causes decreased binding of Stat4 to the IFN-γ promoter and reduced expression of IFN-γ mRNA and protein. Consequently, all Mk3-/- mice challenged with the Thl-inducing influenza A virus (IAV) survived the WT LD50 virus dose. The reduced disease severity in the Mk3-/- mice was accompanied by a > 10-fold reduction in viral lung titer and an increase in the number of activated NK cells and enhanced Th1 activation of CD4 T cells. Thus, our data describe the protein kinase MK3 as a novel regulator of the innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Heme oxygenase 1 (HO-1) is the pivotal catalyst for the primary and rate-determining step in heme catabolism, playing a crucial role in mitigating heme-induced oxidative damage. Pathogenic variants in the HMOX1 gene which encodes HO-1, are responsible for a severe, multisystem disease characterized by recurrent inflammatory episodes, organ failure, and an ultimately fatal course. Chronic hemolysis and abnormally low bilirubin levels are cardinal laboratory features of this disorder. In this study, we describe a patient with severe interstitial lung disease, frequent episodes of hyperinflammation non-responsive to immunosuppression, and fatal pulmonary hemorrhage. Employing exome sequencing, we identified two protein truncating variants in HMOX1 , c.262_268delinsCC (p.Ala88Profs*51) and a previously unreported variant, c.55dupG (p.Glu19Glyfs*14). Functional analysis in patient-derived lymphoblastoid cells unveiled the complete absence of HO-1 protein expression and a marked reduction in cell viability upon exposure to hemin. These findings confirm the pathogenicity of the identified HMOX1 variants, further underscoring their association with severe pulmonary manifestations . This study describes the profound clinical consequences stemming from disruptions in redox metabolism., Competing Interests: The authors have no conflicts of interest to disclose., (© 2023 The Authors.)