Enhanced ApcMin/+ adenoma formation after epithelial CUL4B deletion by recruitment of myeloid-derived suppressor cells.

Colorectal cancer (CRC) stands as a prevalent malignancy globally. A pivotal event in CRC pathogenesis involves the loss-of-function mutation in the APC gene, leading to the formation of benign polyps. Despite the well-established role of APC, the contribution of CUL4B to CRC initiation in the pre-tumorous stage remains poorly understood. In this investigation, we generated a murine model by crossing ApcMin/+ mice with Cul4bΔIEC mice to achieve specific deletion of Cul4b in the gut epithelium against an ApcMin/+ background. By employing histological methods, RNA-sequencing (RNA-seq), and flow cytometry, we assessed alterations and characterized the immune microenvironment. Our results unveiled that CUL4B deficiency in gut epithelium expedited ApcMin/+ adenoma formation. Notably, CUL4B in adenomas restrained the accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). In vivo inhibition of MDSCs significantly delayed the growth of CUL4B deleted ApcMin/+ adenomas. Furthermore, the addition of MDSCs to in vitro cultured ApcMin/+; Cul4bΔIEC adenoma organoids mitigated their alterations. Mechanistically, CUL4B directly interacted with the promoter of Csf3, the gene encoding granulocyte-colony stimulating factor (G-CSF) by coordinating with PRC2. Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating ApcMin/+ adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.

Neutrophil-Driven M2-Like Macrophages Are Critical for Skin Fibrosis in a Systemic Sclerosis Model.

Systemic sclerosis (SSc) is a challenging autoimmune disease characterized by progressive fibrosis affecting the skin and internal organs. Despite the known infiltration of macrophages and neutrophils, their precise contributions to SSc pathogenesis remain elusive. In this study, we elucidated that CD206hiMHCIIlo M2-like macrophages constitute the predominant pathogenic immune cell population in the fibrotic skin of a bleomycin-induced SSc mouse model. These cells emerged as pivotal contributors to the profibrotic response by orchestrating the production of TGF-ß1 through a MerTK signaling-dependent manner. Notably, we observed that neutrophil infiltration was a prerequisite for accumulation of M2-like macrophages. Strategies such as neutrophil depletion or inhibition of CXCR1/2 were proven effective in reducing M2-like macrophages, subsequently mitigating SSc progression. Detailed investigations revealed that in fibrotic skin, neutrophil-released neutrophil extracellular traps were responsible for the differentiation of M2-like macrophages. Our findings illuminate the significant involvement of the neutrophil-macrophage-fibrosis axis in SSc pathogenesis, offering critical information for the development of potential therapeutic strategies.

Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment.

BACKGROUND AND AIMS: RAD51 recombinase (RAD51) is a highly conserved DNA repair protein and is indispensable for embryonic viability. As a result, the role of RAD51 in liver development and function is unknown. Our aim was to characterize the function of RAD51 in postnatal liver development. APPROACH AND RESULTS: RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in chronic liver diseases. We generated a hepatocyte-specific Rad51 deletion mouse model using Alb -Cre ( Rad51 -conditional knockout (CKO)) and Adeno-associated virus 8-thyroxine-binding globulin-cyclization recombination enzyme to evaluate the function of RAD51 in liver development and regeneration. The phenotype in Rad51 -CKO mice is dependent on CRE dosage, with Rad51fl/fl ; Alb -Cre +/+ manifesting a more severe phenotype than the Rad51fl/fl ; Alb -Cre +/- mice. RAD51 deletion in postnatal hepatocytes results in aborted mitosis and early onset of pathological polyploidization that is associated with oxidative stress and cellular senescence. Remarkable liver fibrosis occurs spontaneously as early as in 3-month-old Rad51fl/fl ; Alb -Cre +/+ mice. While liver regeneration is compromised in Rad51 -CKO mice, they are more tolerant of carbon tetrachloride-induced hepatic injury and resistant to diethylnitrosamine/carbon tetrachloride-induced HCC. A chronic inflammatory microenvironment created by the senescent hepatocytes appears to activate ductular reaction the transdifferentiation of cholangiocytes to hepatocytes. The newly derived RAD51 functional immature hepatocytes proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. CONCLUSIONS: Our results demonstrate a novel function of RAD51 in liver development, homeostasis, and tumorigenesis. The Rad51 -CKO mice represent a unique genetic model for premature liver senescence, fibrosis, and hepatocellular carcinogenesis.

Splicing Factor PQBP1 Curtails BAX Expression to Promote Ovarian Cancer Progression.

Splicing factor polyglutamine binding protein-1 (PQBP1) is abundantly expressed in the central nervous system during development, and mutations in the gene cause intellectual disability. However, the roles of PQBP1 in cancer progression remain largely unknown. Here, it is shown that PQBP1 overexpression promotes tumor progression and indicates worse prognosis in ovarian cancer. Integrative analysis of spyCLIP-seq and RNA-seq data reveals that PQBP1 preferentially binds to exon regions and modulates exon skipping. Mechanistically, it is shown that PQBP1 regulates the splicing of genes related to the apoptotic signaling pathway, including BAX. PQBP1 promotes BAX exon 2 skipping to generate a truncated isoform that undergoes degradation by nonsense-mediated mRNA decay, thus making cancer cells resistant to apoptosis. In contrast, PQBP1 depletion or splice-switching antisense oligonucleotides promote exon 2 inclusion and thus increase BAX expression, leading to inhibition of tumor growth. Together, the results demonstrate an oncogenic role of PQBP1 in ovarian cancer and suggest that targeting the aberrant splicing mediated by PQBP1 has therapeutic potential in cancer treatment.

SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation.

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, were decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondrial mass but promoted glycolysis in an SOD2-dependent manner. MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance the immunosuppressive activity of MSCs in the inflammatory microenvironment.

Glucocorticoid activates STAT3 and NF-κB synergistically with inflammatory cytokines to enhance the anti-inflammatory factor TSG6 expression in mesenchymal stem/stromal cells.

Glucocorticoid (GC) is essential for maintaining immune homeostasis. While GC is known to regulate the expression of genes related to inflammation in immune cells, the effects of GC, especially in the presence of inflammation, on non-immune cells remain largely unexplored. In particular, the impact of GC on inflammatory cytokine-induced immune modulatory responses of tissue stromal cells is unknown, though it has been widely used to modulate tissue injuries. Here we found that GC could enhance the expression of TSG6, a vital tissue repair effector molecule, in IFNγ and TNFα treated human umbilical cord (UC)-MSCs. NF-κB activation was found to be required for GC-augmented TSG6 upregulation. STAT3, but not STAT1, was also found to be required for the TSG6 upregulation in MSCs exposed to IFNγ, TNFα and GC. Moreover, the phosphorylation (activation) of STAT3 was attenuated when NF-κB was knocked down. Importantly, human UC-MSCs pretreated with a cocktail containing GC, IFNγ, and TNFα could significantly enhance the therapeutic effect of human UC-MSCs in an acute lung injury mouse model, as reflected by reduced infiltration of immune cells and down-regulation of iNOS in macrophages in the lung. Together, the findings reveal a novel link between GR, NF-κB and STAT3 in regulating the immunomodulatory and regenerative properties of MSCs, providing novel information for the understanding and treatment of inflammatory conditions.

Dying to Defend: Neutrophil Death Pathways and their Implications in Immunity.

Neutrophils, accounting for ≈70% of human peripheral leukocytes, are key cells countering bacterial and fungal infections. Neutrophil homeostasis involves a balance between cell maturation, migration, aging, and eventual death. Neutrophils undergo different death pathways depending on their interactions with microbes and external environmental cues. Neutrophil death has significant physiological implications and leads to distinct immunological outcomes. This review discusses the multifarious neutrophil death pathways, including apoptosis, NETosis, pyroptosis, necroptosis, and ferroptosis, and outlines their effects on immune responses and disease progression. Understanding the multifaceted aspects of neutrophil death, the intersections among signaling pathways and ramifications of immunity will help facilitate the development of novel therapeutic methods.

PML-mediated nuclear loosening permits immunomodulation of mesenchymal stem/stromal cells under inflammatory conditions.

Nuclear configuration plays a critical role in the compartmentalization of euchromatin and heterochromatin and the epigenetic regulation of gene expression. Under stimulation by inflammatory cytokines IFN-γ and TNF-α, human mesenchymal stromal cells (hMSCs) acquire a potent immunomodulatory function enabled by drastic induction of various effector genes, with some upregulated several magnitudes. However, whether the transcriptional upregulation of the immunomodulatory genes in hMSCs exposed to inflammatory cytokines is associated with genome-wide nuclear reconfiguration has not been explored. Here, we demonstrate that hMSCs undergo remarkable nuclear reconfiguration characterized by an enlargement of the nucleus, downregulation of LMNB1 and LMNA/C, decondensation of heterochromatin, and derepression of repetitive DNA. Interestingly, promyelocytic leukaemia-nuclear bodies (PML-NBs) were found to mediate the nuclear reconfiguration of hMSCs triggered by the inflammatory cytokines. Significantly, when PML was depleted, the immunomodulatory function of hMSCs conferred by cytokines was compromised, as reflected by the attenuated expression of effector molecules in hMSCs and their failure to block infiltration of immune cells to lipopolysaccharide (LPS)-induced acute lung injury. Our results indicate that the immunomodulatory function of hMSCs conferred by inflammatory cytokines requires PML-mediated chromatin loosening.

Hyaluronic acid metabolism and chemotherapy resistance: recent advances and therapeutic potential.

Hyaluronic acid (HA) is a major component of the extracellular matrix, providing essential mechanical scaffolding for cells and, at the same time, mediating essential biochemical signals required for tissue homeostasis. Many solid tumors are characterized by dysregulated HA metabolism, resulting in increased HA levels in cancer tissues. HA interacts with several cell surface receptors, such as cluster of differentiation 44 and receptor for hyaluronan-mediated motility, thus co-regulating important signaling pathways in cancer development and progression. In this review, we describe the enzymes controlling HA metabolism and its intracellular effectors emphasizing their impact on cancer chemotherapy resistance. We will also explore the current and future prospects of HA-based therapy, highlighting the opportunities and challenges in the field.

Spliceosome component Usp39 contributes to hepatic lipid homeostasis through the regulation of autophagy.

Regulation of alternative splicing (AS) enables a single transcript to yield multiple isoforms that increase transcriptome and proteome diversity. Here, we report that spliceosome component Usp39 plays a role in the regulation of hepatocyte lipid homeostasis. We demonstrate that Usp39 expression is downregulated in hepatic tissues of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) subjects. Hepatocyte-specific Usp39 deletion in mice leads to increased lipid accumulation, spontaneous steatosis and impaired autophagy. Combined analysis of RNA immunoprecipitation (RIP-seq) and bulk RNA sequencing (RNA-seq) data reveals that Usp39 regulates AS of several autophagy-related genes. In particular, deletion of Usp39 results in alternative 5' splice site selection of exon 6 in Heat shock transcription factor 1 (Hsf1) and consequently its reduced expression. Importantly, overexpression of Hsf1 could attenuate lipid accumulation caused by Usp39 deficiency. Taken together, our findings indicate that Usp39-mediated AS is required for sustaining autophagy and lipid homeostasis in the liver.

p63: a crucial player in epithelial stemness regulation.

Epithelial tissue homeostasis is closely associated with the self-renewal and differentiation behaviors of epithelial stem cells (ESCs). p63, a well-known marker of ESCs, is an indispensable factor for their biological activities during epithelial development. The diversity of p63 isoforms expressed in distinct tissues allows this transcription factor to have a wide array of effects. p63 coordinates the transcription of genes involved in cell survival, stem cell self-renewal, migration, differentiation, and epithelial-to-mesenchymal transition. Through the regulation of these biological processes, p63 contributes to, not only normal epithelial development, but also epithelium-derived cancer pathogenesis. In this review, we provide an overview of the role of p63 in epithelial stemness regulation, including self-renewal, differentiation, proliferation, and senescence. We describe the differential expression of TAp63 and ΔNp63 isoforms and their distinct functional activities in normal epithelial tissues and in epithelium-derived tumors. Furthermore, we summarize the signaling cascades modulating the TAp63 and ΔNp63 isoforms as well as their downstream pathways in stemness regulation.

MHC class Ib-restricted CD8+ T cells possess strong tumoricidal activities.

The importance of classical CD8+ T cells in tumor eradication is well acknowledged. However, the anti-tumor activity of MHC (major histocompatibility complex) Ib-restricted CD8+ T (Ib-CD8+ T) cells remains obscure. Here, we show that CX3CR1-expressing Ib-CD8+ T cells (Ib-restricted CD8+ T cells) highly express cytotoxic factors, austerely resist exhaustion, and effectively eliminate various tumors. These Ib-CD8+ T cells can be primed by MHC Ia (MHC class Ia molecules) expressed on various cell types for optimal activation in a Tbet-dependent manner. Importantly, MHC Ia does not allogeneically activate Ib-CD8+ T cells, rather, sensitizes these cells for T cell receptor activation. Such effects were observed when MHC Ia+ cells were administered to tumor-bearing Kb-/-Db-/-mice. A similar population of tumoricidal CX3CR1+CD8+ T cells was identified in wild-type mice and melanoma patients. Adoptive transfer of Ib-CD8+ T cells to wild-type mice inhibited tumor progression without damaging normal tissues. Taken together, we demonstrate that MHC class Ia can prime Ib-CD8+ T cells for robust tumoricidal activities.

Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan.

Chemotherapy resistance represents a major cause of therapeutic failure and mortality in cancer patients. Mesenchymal stromal cells (MSCs), an integral component of tumor microenvironment, are known to promote drug resistance. However, the detailed mechanisms remain to be elucidated. Here, we found that MSCs confer breast cancer resistance to doxorubicin by diminishing its intratumoral accumulation. Hyaluronan (HA), a major extracellular matrix (ECM) product of MSCs, was found to mediate the chemoresistant effect. The chemoresistant effect of MSCs was abrogated when hyaluronic acid synthase 2 (HAS2) was depleted or inhibited. Exogenous HA also protected tumor grafts from doxorubicin. Molecular dynamics simulation analysis indicates that HA can bind with doxorubicin, mainly via hydrophobic and hydrogen bonds, and thus reduce its entry into breast cancer cells. This mechanism is distinct from the reported chemoresistant effect of HA via its receptor on cell surface. High HA serum levels were also found to be positively associated with chemoresistance in breast cancer patients. Our findings indicate that the HA-doxorubicin binding dynamics can confer cancer cells chemoresistance. Reducing HA may enhance chemotherapy efficacy.

Nitric oxide-dependent immunosuppressive function of thymus-derived mesenchymal stromal/stem cells.

BACKGROUND: The thymus is required for T cell development and the formation of the adaptive immunity. Stromal cells, which include thymic epithelial cells (TECs) and mesenchymal stromal cells (MSCs), are essential for thymic function. However, the immunomodulatory function of thymus-derived MSCs (T-MSCs) has not been fully explored. METHODS: MSCs were isolated from mouse thymus and their general characteristics including surface markers and multi-differentiation potential were characterized. The immunomodulatory function of T-MSCs stimulated by IFN-γ and TNF-α was evaluated in vitro and in vivo. Furthermore, the spatial distribution of MSCs in the thymus was interrogated by using tdTomato-flox mice corssed to various MSC lineage Cre recombinase lines. RESULTS: A subset of T-MSCs express Nestin, and are mainly distributed in the thymic medulla region and cortical-medulla junction, but not in the capsule. The Nestin-positive T-MSCs exhibit typical immunophenotypic characteristics and differentiation potential. Additionally, when stimulated with IFN-γ and TNF-α, they can inhibit activated T lymphocytes as efficiently as BM-MSCs, and this function is dependent on the production of nitric oxide (NO). Additionally, the T-MSCs exhibit a remarkable therapeutic efficacy in acute liver injury and inflammatory bowel disease (IBD). CONCLUSIONS: Nestin-positive MSCs are mainly distributed in medulla and cortical-medulla junction in thymus and possess immunosuppressive ability upon stimulation by inflammatory cytokines. The findings have implications in understanding the physiological function of MSCs in thymus.

Hippo Pathway Activation in Aged Mesenchymal Stem Cells Contributes to the Dysregulation of Hepatic Inflammation in Aged Mice.

Aging is always accompanied by chronic diseases which probably attribute to long-term chronic inflammation in the aging body. Whereas, the mechanism of chronic inflammation in aging body is still obscure. Mesenchymal stem cells (MSCs) are capable of local chemotaxis to sites of inflammation and play a powerful role in immune regulation. Whether degeneration of MSCs in the aging body is associated with unbalanced inflammation is still not clear. In this study, immunosuppressive properties of aged MSCs are found to be repressed. The impaired immunosuppressive function of aged MSCs is associated with lower expression of the Hippo effector Yes-associated protein 1 (YAP1) and its target gene signal transducer and activator of transcription 1 (STAT1). YAP1 regulates the transcription of STAT1 through binding with its promoter. In conclusion, a novel YAP1/STAT1 axis maintaining immunosuppressive function of MSCs is revealed and impairment of this signal pathway in aged MSCs probably resulted in higher inflammation in aged mice liver.

NAD+ salvage governs the immunosuppressive capacity of mesenchymal stem cells.

Mesenchymal stem/stromal cells (MSCs) possess robust immunoregulatory functions and are promising therapeutics for inflammatory disorders. This capacity is not innate but is activated or 'licensed' by inflammatory cytokines. The licensing mechanism remains unclear. Here, we examined whether inflammatory cytokines metabolically reprogrammed MSCs to confer this immunoregulatory capacity. In response to stimulation by inflammatory cytokines, MSCs exhibited a dramatic increase in the consumption of glucose, which was accompanied by an enhanced use of nicotinamide adenine dinucleotide (NAD+) and increased expression of nicotinamide phosphoribosyltransferase (NAMPT), a central enzyme in the salvage pathway for NAD+ production. When NAD+ synthesis was blocked by inhibiting or depleting NAMPT, the immunosuppressive function of MSCs induced by inflammatory cytokines was greatly attenuated. Consequently, when NAD+ metabolism in MSCs was perturbed, their therapeutic benefit was decreased in mice suffering from inflammatory bowel disease and acute liver injury. Further analysis revealed that NAMPT-driven production of NAD+ was critical for the inflammatory cytokine-induced increase in glycolysis in MSCs. Furthermore, the increase in glycolysis led to succinate accumulation in the tricarboxylic acid cycle, which led to hypoxia-inducible factor 1α (HIF-1α) stabilization and subsequently increased the transcription of key glycolytic genes, thereby persistently maintaining glycolytic flux. This study demonstrated that unlike its proinflammatory role in immune cells, NAD+ metabolism governs the anti-inflammatory function of MSCs during inflammation.

Harnessing metabolism of hepatic macrophages to aid liver regeneration.

Liver regeneration is a dynamic and regulated process that involves inflammation, granulation, and tissue remodeling. Hepatic macrophages, abundantly distributed in the liver, are essential components that actively participate in each step to orchestrate liver regeneration. In the homeostatic liver, resident macrophages (Kupffer cells) acquire a tolerogenic phenotype and contribute to immunological tolerance. Following toxicity-induced damage or physical resection, Kupffer cells as well as monocyte-derived macrophages can be activated and promote an inflammatory process that supports the survival and activation of hepatic myofibroblasts and thus promotes scar tissue formation. Subsequently, these macrophages, in turn, exhibit the anti-inflammatory effects critical to extracellular matrix remodeling during the resolution stage. However, continuous damage-induced chronic inflammation generally leads to hepatic macrophage dysfunction, which exacerbates hepatocellular injury and triggers further liver fibrosis and even cirrhosis. Emerging macrophage-targeting strategies have shown efficacy in both preclinical and clinical studies. Increasing evidence indicates that metabolic rewiring provides substrates for epigenetic modification, which endows monocytes/macrophages with prolonged "innate immune memory". Therefore, it is reasonable to conceive novel therapeutic strategies for metabolically reprogramming macrophages and thus mediate a homeostatic or reparative process for hepatic inflammation management and liver regeneration.

IL4I1-catalyzed tryptophan metabolites mediate the anti-inflammatory function of cytokine-primed human muscle stem cells.

Muscle stem cells (MuSCs) have been demonstrated to exert impressive therapeutic efficacy in disease settings through orchestrating inflammatory microenvironments. Nevertheless, the mechanisms underlying the immunoregulatory property of MuSCs remain largely uncharacterized. Here, we showed that interleukin-4-induced-1 (IL4I1), an essential enzyme that catalyzes indole metabolism in humans, was highly expressed in human MuSCs exposed to IFN-γ and TNF-α. Functionally, the MuSCs were found to inhibit the infiltration of neutrophils into sites of inflammation in a IL4I1-dependent manner and thus ameliorate acute lung injury in mice. Mechanistically, the indole metabolites, including indole-3-pyruvic acid (I3P) and indole-3-aldehyde (I3A), produced by IL4I1, acted as ligands to activate aryl hydrocarbon receptor (AHR), leading to augmented expression of TNF-stimulated gene 6 (TSG-6) in inflammatory cytokine-primed MuSCs. Furthermore, I3P administration alone suppressed neutrophil infiltration into damaged lungs. I3P could also reduce the level of reactive oxygen species in neutrophils. Therefore, our study has uncovered a novel mechanism by which MuSCs acquire their immunoregulatory property and may help to develop or optimize MuSC-based therapies for inflammatory diseases.

Orchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing.

Wound healing is a complex process and encompasses a number of overlapping phases, during which coordinated inflammatory responses following tissue injury play dominant roles in triggering evolutionarily highly conserved principals governing tissue repair and regeneration. Among all nonimmune cells involved in the process, mesenchymal stem/stromal cells (MSCs) are most intensely investigated and have been shown to play fundamental roles in orchestrating wound healing and regeneration through interaction with the ordered inflammatory processes. Despite recent progress and encouraging results, an informed view of the scope of this evolutionarily conserved biological process requires a clear understanding of the dynamic interplay between MSCs and the immune systems in the process of wound healing. In this review, we outline current insights into the ways in which MSCs sense and modulate inflammation undergoing the process of wound healing, highlighting the central role of neutrophils, macrophages, and T cells during the interaction. We also draw attention to the specific effects of MSC-based therapy on different pathological wound healing. Finally, we discuss how ongoing scientific advances in MSCs could be efficiently translated into clinical strategies, focusing on the current limitations and gaps that remain to be overcome for achieving preferred functional tissue regeneration.

NAD+ metabolism-based immunoregulation and therapeutic potential.

Nicotinamide adenine dinucleotide (NAD+) is a critical metabolite that acts as a cofactor in energy metabolism, and serves as a cosubstrate for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ metabolism can regulate functionality attributes of innate and adaptive immune cells and contribute to inflammatory responses. Thus, the manipulation of NAD+ bioavailability can reshape the courses of immunological diseases. Here, we review the basics of NAD+ biochemistry and its roles in the immune response, and discuss current challenges and the future translational potential of NAD+ research in the development of therapeutics for inflammatory diseases, such as COVID-19.