There exists only one tumor necrosis factor

Tumor necrosis factor (TNF) is an important proinflammatory and immunoregulatory cytokine with several unique protective and homeostatic functions. Since TNF is a mediator of several pathologies and is a part of “cytokine storm”, its significance for clinical immunology is due to the fact that this cytokine is a target of commonly used anti-cytokine therapy in autoimmune and inflammatory diseases. In scientific literature and textbooks TNF is often goes as “TNFa”, implying the existence of at least TNFβ (indeed, such term was used for about 10 years in 80s and 90s to designate lymphotoxin). However, already 25 years ago such designation of lymphotoxin was cancelled “on scientific grounds”. Therefore, both in Russian and in English the term TNF should be used without “alpha”. Labels of the reagents related to TNFb that are offered by commercial companies are misleading

COVID-19 therapy: from myths to reality and hopes

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, is unprecedented for the 21st century and has already affected countries with a total population of billions of people. The number of infected has already surpassed 30 million people and the number of deaths has exceeded 1 million. Unfor-tunately, Russia is still one of the five countries with the largest number of infected people, although mortality from COVID-19 is significantly lower than in many other countries. Since the virus and the pathogenesis caused by it have a lot of new and unexpected features, high-tech and specific anti-viral drugs and vaccines have not yet been created. The most promising targets for future drug development are enzymes necessary for the life cycle of this particular virus (such as components of the replicase complex or viral proteases). Unexpected circumstances are pushing the evaluation of a number of previously developed and existing drugs directed toward other RNA viruses, some of which have already been shown effective in clinical trials against SARS-CoV-2. There is no doubt that soon prototypes of drugs of this class with higher specificity and effective-ness will be found. Another group of potential drugs are known drugs that are directed against various aspects of the pathogenesis caused by SARS-CoV-2, in particular, cytokine storm or coagulopathy. It should be emphasized that the genome of the virus encodes about 10 additional proteins, some of which may be related to unusual aspects of pathogenesis during COVID-19. Basic research should determine which of these proteins can be targets for specific therapy. Finally, the fact that neutralizing antibodies are found in the blood plasma of many patients and can be used for the prevention and treatment of COVID-19, indicates the potential of using recombinant neutralizing antibodies as drugs, and secondly, confirms the possibility of creating effective vaccines. This mini-review discusses therapeutic approaches and the status of clinical trials using drugs that already existed before the pandemic and were originally developed against other infectious agents or for the treatment of autoimmune pathologies. These drugs are part of today's arsenal in therapeutic protocols and are used in an attempt to cope with the COVID-19 epidemic in different countries

Itaconate-mediated inhibition of succinate dehydrogenase regulates cytokine production in LPS-induced inflammation

Itaconate is an immunoregulatory metabolite produced by myeloid cells and plays a key role in the regulation of the immune response. Itaconate, on the one hand, is able to suppress the activity of succinate dehydrogenase (SDH), thereby making a significant contribution to the metabolic reprogramming of the cell. On the other hand, itaconate can regulate the activity of a number of transcription factors and transcription regulators, thereby affecting gene expression. In most experimental studies, itaconate has been characterized predominantly as an anti-inflammatory agent. In particular, itaconate produced by activated macrophages inhibits the production of cytokines TNF, IL-1b, IL-6, IL-10. However, some evidence suggests a pro- inflammatory role for itaconate in a number of mouse disease models. Thus, the deletion of the Acod1 gene responsible for the production of itaconate leads to the suppression of the production of TNF and IL-6 in the mouse polymicrobial sepsis model, which means that in the context of inflammation in vivo, itaconate can act as an inducer of pro-inflammatory cytokines. The mechanism of itaconate regulation of cytokine production in systemic inflammation remains unexplored. In this work, we have shown that injection of itaconate and its derivative dimethyl itaconate into mice, followed by induction of inflammation by bacterial lipopolysaccharide (LPS), leads to changes in the content of cytokines in the blood. Interestingly, the systemic production of IL-6 and IL-10 in response to itaconate is increased, contrary to the results previously obtained in cell cultures. At the same time, IFNg production, on the contrary, is suppressed. Apparently, itaconate regulates the production of cytokines in vivo by suppressing the activity of SDH. Injection of the SDH inhibitor, dimethylmalonate, followed by induction of inflammation in mice, results in similar changes in blood cytokines observed in response to itaconate: increased production of IL-6, IL-10 and suppression of IFNg production. On the contrary, the addition of succinate, a SDH substrate, leads to the opposite effect on cytokine production. Thus, it can be assumed that the observed effects of itaconate on cytokine production in the model of LPS-induced inflammation are mediated by its ability to inhibit SDH. These results help to understand the controversial role of itaconate in inflammation and shed light on a previously undescribed relationship between SDH and cytokine production in inflammation in vivo

Akkermansia muciniphila - friend or foe in colorectal cancer?

Akkermansia muciniphila is a gram-negative anaerobic bacterium, which represents a part of the commensal human microbiota. Decline in the abundance of A. muciniphila among other microbial species in the gut correlates with severe systemic diseases such as diabetes, obesity, intestinal inflammation and colorectal cancer. Due to its mucin-reducing and immunomodulatory properties, the use of probiotics containing Akkermansia sp. appears as a promising approach to the treatment of metabolic and inflammatory diseases. In particular, a number of studies have focused on the role of A. muciniphila in colorectal cancer. Of note, the results of these studies in mice are contradictory: some reported a protective role of A. muciniphila in colorectal cancer, while others demonstrated that administration of A. muciniphila could aggravate the course of the disease resulting in increased tumor burden. More recent studies suggested the immunomodulatory effect of certain unique surface antigens of A. muciniphila on the intestinal immune system. In this Perspective, we attempt to explain how A. muciniphila contributes to protection against colorectal cancer in some models, while being pathogenic in others. We argue that differences in the experimental protocols of administration of A. muciniphila, as well as viability of bacteria, may significantly affect the results. In addition, we hypothesize that antigens presented by pasteurized bacteria or live A. muciniphila may exert distinct effects on the barrier functions of the gut. Finally, A. muciniphila may reduce the mucin barrier and exerts combined effects with other bacterial species in either promoting or inhibiting cancer development

Changes in the composition of the intestinal microbiota, associated with IL-6 deficiency

Interleukin-6 (IL-6) is a broad-spectrum cytokine involved in the immune, nervous, and endocrine regulation of many biological processes. IL-6 performs both homeostatic and pathogenic functions. It is one of the key factors in the cytokine storm in COVID-19, and it also controls the production of acute phase proteins during inflammation. IL-6 is involved in the maintenance of intestinal homeostasis and is required for both the induction of inflammation and the repair of the injured intestinal tissue. In turn, the commensal microbiota, represented by eukaryotes, prokaryotes, and viruses, is one of the key factors modulating the immune response in the gut. The predominance of certain groups of commensal microorganisms is associated with the development of intestinal inflammation, while probiotics and antibiotics are successfully used to control inflammatory bowel disease. IL-6 is also necessary to maintain the barrier function of the intestine by modulating the proliferation of intestinal cells, which is necessary for their timely renewal both in homeostasis and inflammation. It has been established that the genetic inactivation of IL6 contributes to the development of intestinal inflammation, while the involvement of IL-6 in the control of the gut microbiota composition remains unclear. To investigate this issue, we analyzed stool samples from wild-type naive mice and mice deficient in IL6 (IL-6 KO) generated on the C57Bl/6 genetic background. It has been determined that IL-6 KO shows significant changes in some taxonomic groups of commensals, which may explain the sensitivity of IL-6 KO to the development of colitis. Interestingly, the relative contents of Firmicutes and Clostridiales are significantly reduced, whereas Bacteroides are increased in IL-6 KO as compared with wild-type mice. Our data on the reduction of Firmicutes, Lactobacillaceae, and other large taxa in IL-6 deficient mice suggest that the microbiota composition of IL-6 KO mice is somewhat similar to that of mice with chronic intestinal inflammation. Our study serves as a perspective for further research on the contribution of IL-6-mediated changes in the microbiota composition to the maintenance of intestinal homeostasis and the development of chronic gut inflammation

Macrophages from naked mole-rat possess distinct immunometabolic signatures upon polarization

The naked mole-rat (NMR) is a unique long-lived rodent which is highly resistant to age-associated disorders and cancer. The immune system of NMR possesses a distinct cellular composition with the prevalence of myeloid cells. Thus, the detailed phenotypical and functional assessment of NMR myeloid cell compartment may uncover novel mechanisms of immunoregulation and healthy aging. In this study gene expression signatures, reactive nitrogen species and cytokine production, as well as metabolic activity of classically (M1) and alternatively (M2) activated NMR bone marrow-derived macrophages (BMDM) were examined. Polarization of NMR macrophages under pro-inflammatory conditions led to expected M1 phenotype characterized by increased pro-inflammatory gene expression, cytokine production and aerobic glycolysis, but paralleled by reduced production of nitric oxide (NO). Under systemic LPS-induced inflammatory conditions NO production also was not detected in NMR blood monocytes. Altogether, our results indicate that NMR macrophages are capable of transcriptional and metabolic reprogramming under polarizing stimuli, however, NMR M1 possesses species-specific signatures as compared to murine M1, implicating distinct adaptations in NMR immune system

Reproductive effects of the tumor necrosis factor (TNF) deficiency in mice

TNF is a multifunctional cytokine that, at physiological concentrations, maintains the balance between apoptosis and survival of male germ cells and, at higher concentrations, has adverse effects on various stages of the reproductive process. Although ant-cytokine therapies have been used in millions of patients, the consequences of cytokine deficiency for reproductive functions are poorly understood and need attention. In this work, we have studied behavioral interactions between males and females, spermatogenesis, male fertility, and embryonic developmental characteristics of the progeny in TNFα knockout mice (TNF-/-). We have demonstrated that TNF is involved in the regulation of sexual behavior, spermatogenesis, pre- and postimplantation development. Complete TNF deficiency led to decreased reproductive efficiency: a lower number of viable embryos were observed in TNF-/- mice than in wild-type mice. The decrease in fertility was caused by preimplantation embryo loss in TNF-/- mice. Preimplantation loss in females might be caused by asospermia in TNF-/- males. Additionally, the sensitivity of reproductive functions to female stimuli was different between TNF-/- mice and wild-type mice, while interactions with females increased the concentrations of sper­matozoids in both TNF-/- and wild-type mice. Still higher levels were observed in knockout animals, which led to increase in the number of immature spermatozoids in epididymides

Novel Biodegradable Polymeric Microparticles Facilitate Scarless Wound Healing by Promoting Re-epithelialization and Inhibiting Fibrosis

Despite decades of research, the goal of achieving scarless wound healing remains elusive. One of the approaches, treatment with polymeric microcarriers, was shown to promote tissue regeneration in various in vitro models of wound healing. The in vivo effects of such an approach are attributed to transferred cells with polymeric microparticles functioning merely as inert scaffolds. We aimed to establish a bioactive biopolymer carrier that would promote would healing and inhibit scar formation in the murine model of deep skin wounds. Here we characterize two candidate types of microparticles based on fibroin/gelatin or spidroin and show that both types increase re-epithelialization rate and inhibit scar formation during skin wound healing. Interestingly, the effects of these microparticles on inflammatory gene expression and cytokine production by macrophages, fibroblasts, and keratinocytes are distinct. Both types of microparticles, as well as their soluble derivatives, fibroin and spidroin, significantly reduced the expression of profibrotic factors Fgf2 and Ctgf in mouse embryonic fibroblasts. However, only fibroin/gelatin microparticles induced transient inflammatory gene expression and cytokine production leading to an influx of inflammatory Ly6C+ myeloid cells to the injection site. The ability of microparticle carriers of equal proregenerative potential to induce inflammatory response may allow their subsequent adaptation to treatment of wounds with different bioburden and fibrotic content

Expression of lymphotoxin beta governs immunity at two distinct levels

Interaction of lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice conditionally deficient for LTbeta on different lymphocyte subsets to determine how the LTbeta-dependent lymphoid structure influences immune reactivity. All conditionally LTbeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LTbeta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LTbeta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LTbeta expression influences immune reactivity at two distinct levels: (i) Expression of LTbeta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LTbeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread