CD38 is a molecule that can act as an enzyme, with NAD-depleting and intracellular signaling activity, or as a receptor with adhesive functions. CD38 can be found expressed either on the cell surface, where it may face the extracellular milieu or the cytosol, or in intracellular compartments, such as endoplasmic reticulum, nuclear membrane, and mitochondria. The main expression of CD38 is observed in hematopoietic cells, with some cell-type specific differences between mouse and human. The role of CD38 in immune cells ranges from modulating cell differentiation to effector functions during inflammation, where CD38 may regulate cell recruitment, cytokine release, and NAD availability. In line with a role in inflammation, CD38 appears to also play a critical role in inflammatory processes during autoimmunity, although whether CD38 has pathogenic or regulatory effects varies depending on the disease, immune cell, or animal model analyzed. Given the complexity of the physiology of CD38 it has been difficult to completely understand the biology of this molecule during autoimmune inflammation. In this review, we analyze current knowledge and controversies regarding the role of CD38 during inflammation and autoimmunity and novel molecular tools that may clarify current gaps in the field.

/pdf/cd38-an-immunomodulatory-molecule-in-inflammation-and-3rngn4u3ru.pdf

CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity.

Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets.

CD38 is a multifunctional protein widely expressed in cells from the immune system and as a soluble form in biological fluids. CD38 expression is up-regulated by an array of inflammatory mediators, and it is frequently used as a cell activation marker. Studies in animal models indicate that CD38 functional expression confers protection against infection by several bacterial and parasitic pathogens. In addition, infectious complications are associated with anti-CD38 immunotherapy. Although CD38 displays receptor and enzymatic activities that contribute to the establishment of an effective immune response, recent work raises the possibility that CD38 might also enhance the immunosuppressive potential of regulatory leukocytes. This review integrates the current knowledge on the diversity of functions mediated by CD38 in the host defense to infection.

/pdf/roles-of-cd38-in-the-immune-response-to-infection-n7cnjhlmzp.pdf

Roles of CD38 in the Immune Response to Infection.

Aging is a complex process that involves dysfunction on multiple levels, all of which seem to converge on inflammation Macrophages are intimately involved in initiating and resolving inflammation, and their dysregulation with age is a primary contributor to inflammaging—a state of chronic, low-grade inflammation that develops during aging Among the age-related changes that occur to macrophages are a heightened state of basal inflammation and diminished or hyperactive inflammatory responses, which seem to be driven by metabolic-dependent epigenetic changes In this review article we provide a brief overview of mitochondrial functions and age-related changes that occur to macrophages, with an emphasis on how the inflammaging environment, senescence, and NAD decline can affect their metabolism, promote dysregulation, and contribute to inflammaging and age-related pathologies

/pdf/macrophage-immunometabolism-and-inflammaging-roles-of-z43n8xowmr.pdf

Macrophage Immunometabolism and Inflammaging: Roles of Mitochondrial Dysfunction, Cellular Senescence, CD38, and NAD.

Abstract Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) significantly increases morbidity and mortality. Growing evidence suggests that fatty acid-binding protein 4 (FABP4) is critically involved in kidney diseases, while its role in septic AKI remains unknown. Here, FABP4 was mainly upregulated in renal tubular epithelial cells (RTECs) following cecal ligation and puncture (CLP)- or lipopolysaccharide (LPS)-induced septic AKI. FABP4 inhibition by genetic deletion or BMS309403 treatment both attenuated kidney dysfunction and pathological injury in CLP- or LPS-treated mice. Notably, RTEC-specific deletion of FABP4 also showed similar renoprotective effects. Moreover, FABP4 inhibition alleviated inflammation and apoptosis in CLP-injured kidneys and LPS-stimulated mouse tubular epithelial cells. Mechanistically, TLR4 blockage improved sepsis-induced kidney injury, as well as suppressed c-Jun phosphorylation and FABP4 expression, where c-Jun knockdown also inhibited LPS-stimulated FABP4 level. Meanwhile, FABP4 inhibition reduced the elevated phosphorylated c-Jun, while the levels of TLR4 and MyD88 were uninfluenced. Collectively, the increased FABP4 in RTECs is dependent on TLR4/c-Jun signaling activation and contributes to kidney injury, by forming a positive feedback loop with c-Jun to aggravate inflammation and apoptosis in septic AKI. Thus, FABP4 may be a therapeutic target for septic AKI. 

/pdf/fatty-acid-binding-protein-4-is-a-therapeutic-target-for-2xp6l81f.pdf

Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis

Gram-negative bacterial sepsis accounts for up to 50% worldwide sepsis that causes hospital mortality. Acute kidney injury (AKI), a common complication of Gram-negative bacterial sepsis, is caused by Toll-like receptor 4 (TLR4) activation. Lipopolysaccharide (LPS) is an endotoxin in Gram-negative bacteria and is recognized specifically by TLR4, which initiates innate immune response. Also, TLR4 signaling pathway activation is essential in response to LPS infection. CD38 is one of the well-known regulators of innate immunity, whose dysregulation contributes to sepsis. Many studies have proven that an attenuated Gram-positive bacterium induces sepsis in a CD38-blocking model. However, the pathogenesis of Gram-negative bacteria-induced sepsis in a CD38-/- mouse model remains unclear. The aim of this study is to investigate whether kidney injury is still attenuated in a LPS-induced CD38-/- sepsis model and identify the potential mechanism. We assess the severity of kidney injury related to proinflammatory cytokine expressions (IFN-γ, TNF-α, IL-1β, and IL-6) in WT and CD38-/- mice. Our results showed more aggravated kidney damage in CD38-/- mice than in WT mice, accompanied with an increase of proinflammatory cytokine expression. In addition, compared with CD38-/-TLR4mut mice, we found an increase of TLR4 expression and mRNA expression of these cytokines in the kidney of CD38-/- mice, although only increased IFN-γ level was detected in the serum. Taken together, these results demonstrated that an increased TLR4 expression in CD38-/- mice could contribute to the aggravation of AKI through boosting of the production of IFN-γ.

Increased TLR4 Expression Aggravates Sepsis by Promoting IFN-γ Expression in CD38-/- Mice.

Aim. The RelB gene plays an important role in guiding the progression of arthritis. We have previously demonstrated that the expression of the RelB gene is decreased significantly in bone marrow DCs of CD38-/- mice. In this study, we demonstrate that the cluster of the differentiation (CD38) gene could be a potentially therapeutic target for autoimmune arthritis. Method. Collagen-induced arthritis (CIA) models were generated with both the wild-type (WT) C57BL/6 and CD38-/- mice. The expression of the RelB gene and maturation of bone marrow-derived dendritic cells (DCs) from the WT and CD38-/- mice were detected. Antigen-specific T cell responses, joint damage, and expression of proinflammatory cytokines were assessed. The effects of the Nuclear Factor Kappa B (NF-κB) transcription factor and its mechanisms were characterized. Results. We demonstrated that in CD38-/- mice, the expression of the RelB gene and major histocompatibility complex II (MHC II) was decreased, accompanied with the inhibited T cell reaction in a mixed lymphocyte reaction (MLR) in bone marrow-derived DCs. Compared to the serious degeneration of the cartilage and the enlarged gap of the cavum articular in WT CIA mice, joint pathological changes of the CD38-/- CIA mice revealed marked attenuation, while the joint structures were well preserved. The preserved effects were observed by the inhibition of proinflammatory cytokines and promotion of anti-inflammatory cytokines. Furthermore, decreased phosphorylation of NF-κB was also observed in CD38-/- CIA mice. Conclusion. We demonstrate that CD38 could regulate CIA through NF-κB and this regulatory molecule could be a novel target for the treatment of autoimmune inflammatory joint disease.

/pdf/cd38-deficiency-downregulates-the-onset-and-pathogenesis-of-2his42ncxg.pdf

CD38 Deficiency Downregulates the Onset and Pathogenesis of Collagen-Induced Arthritis through the NF-κB Pathway

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Increased TLR4 Expression Aggravates Sepsis by Promoting IFN-γ Expression in CD38-/- Mice.

CD38 Deficiency Downregulates the Onset and Pathogenesis of Collagen-Induced Arthritis through the NF-κB Pathway