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Lymphotoxin α and lymphotoxin β (LTs), TNF superfamily members, are expressed in either soluble (LTα3) or membrane‐bound (LTα1β2 or LTα2β1) forms. In the pathological context, LT‐mediated signaling is known to exacerbate autoimmunity by perpetuating inflammation and promoting the formation of tertiary lymphoid organs. Despite this understanding, the exact roles of LTα and LTβ in the pathogenesis of the murine model of multiple sclerosis, and experimental autoimmune encephalomyelitis (EAE), remain controversial. Here, we employed a panel of gene‐modified mice with cell‐type restricted ablation of LTα (targeting both membrane‐bound and soluble forms of LTs) to unravel the contributions of LTs from various lymphoid cells, namely T cells, type 3 innate lymphoid cells (ILC3) and B cells, in EAE. We found that the effects of LTα deletion were dependent on the cellular source. ILC3‐derived lymphotoxins exerted a protective role in EAE by regulating the accumulation of IFN‐ɣ‐ and GM‐CSF‐producing TH cells in the CNS. In contrast, T‐cell‐derived lymphotoxins promoted IL‐17A‐ and GM‐CSF‐mediated TH responses in the periphery, whereas B‐cell‐derived lymphotoxins were pathogenic only in the autoantibody‐mediated EAE model. Collectively, our findings unveil the multifaceted involvement of lymphotoxins in EAE pathogenesis and challenge the view that lymphotoxins play a solely pathogenic role in neuroinflammation. [ABSTRACT FROM AUTHOR]

Itaconate is one of the most studied immunometabolites produced by myeloid cells during inflammatory response. It mediates a wide range of anti-inflammatory and immunoregulatory effects and plays a role in a number of pathological states, including autoimmunity and cancer. Itaconate and its derivatives are considered potential therapeutic agents for the treatment of inflammatory diseases. While immunoregulatory effects of itaconate have been extensively studied in vitro and using knockout mouse models, less is known about how therapeutic administration of this metabolite regulates inflammatory response in vivo. Here, we investigate the immunoregulatory properties of exogenous administration of itaconate and its derivative dimethyl itaconate in a mouse model of lipopolysaccharide-induced inflammation. The data show that administration of itaconate or dimethyl itaconate controls systemic production of multiple cytokines, including increased IL-10 production. However, only dimethyl itaconate was able to suppress systemic production of IFNγ and IL-1β. In contrast to in vitro data, administration of itaconate or dimethyl itaconate in vivo resulted in systemic upregulation of IL-6 in the blood. Electrophilic stress due to itaconate or dimethyl itaconate was not responsible for IL-6 upregulation. However, inhibition of succinate dehydrogenase with dimethyl malonate also resulted in elevated systemic levels of IL-6 and IL-10. Taken together, our study reports a novel effect of exogenous itaconate and its derivative dimethyl itaconate on the production of IL-6 in vivo, with important implications for the development of itaconate-based anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

COVID‐19 is a systemic inflammatory disease initiated by SARS‐CoV‐2 virus infection. Multiple vaccines against the Wuhan variant of SARS‐CoV‐2 have been developed including a whole virion beta‐propiolactone‐inactivated vaccine based on the B.1.1 strain (CoviVac). Since most of the population has been vaccinated by targeting the original or early variants of SARS‐CoV‐2, the emergence of novel mutant variants raises concern over possible evasion of vaccine‐induced immune responses. Here, we report on the mechanism of protection by CoviVac, a whole virion‐based vaccine, against the Omicron variant. CoviVac‐immunized K18‐hACE2 Tg mice were protected against both prototype B.1.1 and BA.1‐like (Omicron) variants. Subsequently, vaccinated K18‐hACE2 Tg mice rapidly cleared the infection via cross‐reactive T‐cell responses and cross‐reactive, non‐neutralizing antibodies recognizing the Omicron variant Spike protein. Thus, our data indicate that efficient protection from SARS‐CoV‐2 variants can be achieved by the orchestrated action of cross‐reactive T cells and non‐neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrixproducing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor [beta]1 (TGF-[beta]1), which prevents the apoptosis of FAPs and induces their differentiation into matrix- producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-[beta]1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF- rich to a TGF-[beta]-rich environment favors fibrotic degeneration of the muscle during chronic injury., Acute skeletal muscle damage triggers a transient phase of extracellular matrix (ECM) remodeling (1), the prompt termination of which is crucial to avoiding pathological fibrosis and consequent tissue degeneration. Recent [...]