SummaryADP-ribosylation is the addition of one or more (up to some hundreds) ADP-ribose moieties to acceptor proteins. There are two major families of enzymes that catalyse this reaction: extracellular ADP-ribosyl-transferases (ARTs), which are bound to the cell membrane by a glycosylphosphatidylinositol anchor or are secreted, and poly(ADP-ribose)-polymerases (PARPs), which are present in the cell nucleus and/or cytoplasm. Recent findings revealed a wide immunological role for ADP-ribosylating enzymes. ARTs, by sensing extracellular NAD concentration, can act as danger detectors. PARP-1, the prototypical representative of the PARP family, known to protect cells from genomic instability, is involved in the development of inflammatory responses and several forms of cell death. PARP-1 also plays a role in adaptive immunity by modulating the ability of dendritic cells to stimulate T cells or by directly affecting the differentiation and functions of T and B cells. Both PARP-1 and PARP-14 (CoaSt6) knockout mice were described to display reduced T helper type 2 cell differentiation and allergic responses. Our recent findings showed that PARP-1 is involved in the differentiation of Foxp3 + regulatory T (Treg) cells, suggesting a role for PARP-1 in tolerance induction. Also ARTs regulate Treg cell homeostasis by promoting Treg cell apoptosis during inflammatory responses. PARP inhibitors ameliorate immune-mediated diseases in several experimental models, including rheumatoid arthritis, colitis, experimental autoimmune encephalomyelitis and allergy. Together these findings show that ADP-ribosylating enzymes, in particular PARP-1, play a pivotal role in the regulation of immune responses and may represent a good target for new therapeutic approaches in immune-mediated diseases.

PARP-1 (poly(ADP-ribose)-polymerase 1), mainly known for its protective role in DNA repair, also regulates inflammatory processes. Notably, defects in DNA repair and chronic inflammation may both predispose to cancer development. On the other hand, inhibition of DNA repair and inflammatory responses can be beneficial in cancer therapy and PARP inhibitors are currently used for their lethal effects on tumor cells. Furthermore, excess of PARP-1 activity has been associated with many tumors and inflammation-related clinical conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases, to name a few. Activation and inhibition of PARP represent, therefore, a double-edged sword that can be exploited for therapeutic purposes. In our review, we will discuss recent findings highlighting the composite multifaceted role of PARP-1 in cancer and inflammation-related diseases.

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On 7 January 2020, researchers isolated and sequenced in China from patients with severe pneumonitis a novel coronavirus, then called SARS-CoV-2, which rapidly spread worldwide, becoming a global health emergency. Typical manifestations consist of flu-like symptoms such as fever, cough, fatigue, and dyspnea. However, in about 20% of patients, the infection progresses to severe interstitial pneumonia and can induce an uncontrolled host-immune response, leading to a life-threatening condition called cytokine release syndrome (CRS). CRS represents an emergency scenario of a frequent challenge, which is the complex and interwoven link between infections and autoimmunity. Indeed, treatment of CRS involves the use of both antivirals to control the underlying infection and immunosuppressive agents to dampen the aberrant pro-inflammatory response of the host. Several trials, evaluating the safety and effectiveness of immunosuppressants commonly used in rheumatic diseases, are ongoing in patients with COVID-19 and CRS, some of which are achieving promising results. However, such a use should follow a multidisciplinary approach, be accompanied by close monitoring, be tailored to patient's clinical and serological features, and be initiated at the right time to reach the best results. Autoimmune patients receiving immunosuppressants could be prone to SARS-CoV-2 infections; however, suspension of the ongoing therapy is contraindicated to avoid disease flares and a consequent increase in the infection risk.

Growing evidence is unveiling a role for poly(ADP-ribose) polymerase (PARP)-1 in the regulation of inflammatory/immune responses. In the current study, we investigated the effects of PARP-1 deficiency on regulatory T cell differentiation. Increased numbers of regulatory CD4+CD25+/Foxp3+ T cells were found in thymus, spleen, and lymph nodes of PARP-1 knockout (KO) mice compared with wild-type (WT) controls. The increased frequency of regulatory T cells in the periphery resulted in impaired CD4 cell proliferation and IL-2 production, which could be restored by CD25+ cell depletion. Phenotype and inhibitory functions of PARP-1 KO regulatory T cells were similar to WT cells, indicating that PARP-1 affects regulatory T cell differentiation rather than function. Purified naive CD4 cells from PARP-1 KO mice stimulated in vitro expressed forkhead box p3 mRNA at higher levels and generated a greater number of Foxp3+ cells (inducible regulatory T [iTreg] cells) than the WT counterpart. This finding was due to a higher rate of naive CD4 cell to Foxp3+ iTreg cell conversion rather than to higher resistance to apoptosis induction. Interestingly, PARP-1 deficiency did not affect retinoid-related orphan receptor-γt mRNA expression and differentiation of purified naive CD4 cells to Th17 cells. PARP-1 KO iTreg cells showed features similar to WT regulatory T cells, suggesting that modulation of PARP-1 during the immune response might be used to induce greater numbers of functional regulatory T cells. In conclusion, our findings represent the first evidence that PARP-1 can affect regulatory T cell differentiation and open new perspectives on potential targets for modulating immune responses.

We demonstrated previously that beta-carotene may affect cell growth by a redox mechanism. The purpose of this study was to determine whether the redox-sensitive transcription factor nuclear factor (NF)-kappaB may be involved in the growth-inhibitory and proapoptotic effects of the carotenoid. To test this hypothesis, human leukemic cells (HL-60) and colon adenocarcinoma cells (LS-174 and WiDr) were treated with beta-carotene, alone or in combination with alpha-tocopherol or N-acetylcysteine, and changes in 1) cell oxidative status, 2) cell growth and apoptosis, 3) DNA-binding activity of NF-kappaB and 4) expression of c-myc, a NF-kappaB target gene involved in apoptosis, were evaluated. In HL-60 cells, beta-carotene induced a significant increase in reactive oxygen species (ROS) production (P < 0.001) and in oxidized glutathione (GSSG) content (P < 0.005) at concentrations >/=10 micro mol/L. These effects were always accompanied by a sustained elevation of NF-kappaB and by a significant inhibition (P < 0.002) of cell growth. NF-kappaB DNA-binding activity increased at 3 h and persisted for at least 48 h. Colon adenocarcinoma cells displayed substantial differences in their sensitivity to beta-carotene, exhibiting increased ROS levels and activation of NF-kappaB at concentrations much lower in LS-174 cells (2.5-5.0 micro mol/L) than in WiDr cells (50-100 micro mol/L). In all cell lines studied, alpha-tocopherol and N-acetylcysteine inhibited the effects of beta-carotene on NF-kappaB, cell growth and apoptosis, and normalized the increased expression of c-myc induced by the carotenoid. These data suggest that the redox regulation of NF-kappaB induced by beta-carotene is involved in the growth-inhibitory and proapoptotic effects of the carotenoid in tumor cells.

Although a large amount of information is available on the activity of CTLA-4 in T cells, the role of this receptor in B cells has not been previously characterized. Our results show that CD40 or LPS stimulation in the presence of IL-4 induces CTLA-4 expression in purified B cells; the maximum level is reached in both membrane and intracellular compartments after 48–72 h. Engagement of the B cell CTLA-4 by immobilized mAb inhibits IgG1 and IgE production and reduces the frequency of IgG1- and IgE-expressing B cells. Cε and Cγ1 germline mRNA expression as well as NF-κB and STAT6 activation, events required for isotype switching, are also inhibited by CTLA-4 engagement. Together these findings show the critical role of CTLA-4 in the control of IL-4-driven isotype switching and suggest new approaches for modulating immediate-type hypersensitivity responses.

Murine CD4+CD25+ T regulatory (Treg) cells were cocultured with CD4+CD25− Th cells and APCs or purified B cells and stimulated by anti-CD3 mAb. Replacement of APCs by B cells did not significantly affect the suppression of CD4+CD25− Th cells. When IL-4 was added to separate cell populations, this cytokine promoted CD4+CD25− Th and CD4+CD25+ Treg cell proliferation, whereas the suppressive competence of CD4+CD25+ Treg cells was preserved. Conversely, IL-4 added to coculture of APCs, CD4+CD25− Th cells, and CD4+CD25+ Treg cells inhibited the suppression of CD4+CD25− Th cells by favoring their survival through the induction of Bcl-2 expression. At variance, suppression was not affected by addition of IL-13, although this cytokine shares with IL-4 a receptor chain. When naive CD4+CD25− Th cells were replaced by Th1 and Th2 cells, cell proliferation of both subsets was equally suppressed, but suppression was less pronounced compared with that of CD4+CD25− Th cells. IL-4 production by Th2 cells was also inhibited. These results indicate that although CD4+CD25+ Treg cells inhibit IL-4 production, the addition of IL-4 counteracts CD4+CD25+ Treg cell-mediated suppression by promoting CD4+CD25− Th cell survival and proliferation.