Publications

Kidney diseases represent a major public health problem, affecting millions of people worldwide. Moreover, the treatment of kidney diseases is burdened by the problematic effects of conventional drug delivery, such as systemic drug toxicity, rapid drug clearance, and the absence of precise targeting of the kidney. Although the use of nanotechnology in medicine is in its early stage and lacks robust translational studies, nanomedicines have already shown great promise as novel drug-delivery systems for the treatment of kidney disease. On the basis of our current knowledge of renal anatomy and physiology, pathophysiology of kidney diseases, and physicochemical characteristics of nanoparticles, an expansive repertoire and wide use of nanomedicines could be developed for kidney diseases in the near future. Some limitations have slowed the transition of these agents from preclinical studies to clinical trials, however. In this review, we summarize the current knowledge on renal drug-delivery systems and recent advances in renal cell targeting; we also demonstrate their important potential as future paradigm-shifting therapies for kidney diseases.

Immune cell microenvironment plays a major role in the aberrant function of immune cells in systemic lupus erythematosus. Zeng and co-authors show that in human and murine lupus, splenic stromal cell-derived acetylcholine switches B cell metabolism to fatty acid oxidation and promotes B cell autoreactivity and disease development.

Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ damage, morbidity and death. Platelets have long been known for their role in primary haemostasis, but they are now also considered to be components of the immune system and to have a central role in the pathogenesis of IMIDs. In patients with IMIDs, platelets are activated by disease-specific factors, and their activation often reflects disease activity. Here we summarize the evidence showing that activated platelets have an active role in the pathogenesis and the progression of IMIDs. Activated platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis. Targeting platelet activation and targeting the interaction of platelets with the immune system are novel and promising therapeutic strategies in IMIDs.

Autoimmune manifestations were reported in people infected with SARS-CoV-2. Repetitive exposure of mice to foreign antigen may lead to the onset of autoimmunity. We therefore investigated whether repetitive exposure to the SARS-CoV-2 spike protein could result in autoimmunity. To address this hypothesis, we repeatedly immunized C57Bl/6 mice with spike protein injected intraperitoneally. At the end of the immunization, mice which received spike protein produced anti-spike IgG but none of them developed anti-dsDNA antibodies or proteinuria. In conclusion, repetitive immunization with SARS-CoV-2 spike protein does not induce autoimmunity in the present mice model. Albeit reassuring, these results need to be confirmed by large epidemiological study evaluating the incidence of autoimmune diseases in individuals with repetitive SARS-CoV-2 antigen exposure.

The deposition of immune complexes, activation of complement and infiltration of the kidney by cells of the adaptive and innate immune systems have long been considered responsible for the induction of kidney damage in autoimmune, alloimmune and other inflammatory kidney diseases. However, emerging findings have highlighted the contribution of resident immune cells and of immune molecules expressed by kidney-resident parenchymal cells to disease processes. Several types of kidney parenchymal cells seem to express a variety of immune molecules with a distinct topographic distribution, which may reflect the exposure of these cells to different pathogenic threats or microenvironments. A growing body of literature suggests that these cells can stimulate the infiltration of immune cells that provide protection against infections or contribute to inflammation - a process that is also regulated by draining kidney lymph nodes. Moreover, components of the immune system, such as autoantibodies, cytokines and immune cells, can influence the metabolic profile of kidney parenchymal cells in the kidney, highlighting the importance of crosstalk in pathogenic processes. The development of targeted nanomedicine approaches that modulate the immune response or control inflammation and damage directly within the kidney has the potential to eliminate the need for systemically acting drugs.

Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD(+), is up-regulated in CD8(+) T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8(+) T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8(+) T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.

PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and inflammation in multiple organs. In this article, we present data on how various mitochondria pathologies are involved in the pathogenesis of the disease including the fact that they serve as a reservoir of autoantigens which contribute to the upending of lymphocyte tolerance. RECENT FINDINGS: Mitochondrial DNA from various cell sources, including neutrophil extracellular traps, platelets, and red blood cells, elicits the production of type I interferon which contributes to breaking of peripheral tolerance. Mitochondrial DNA also serves as autoantigen targeted by autoantibodies. Mutations of mitochondrial DNA triggered by reactive oxygen species induce T cell cross-reactivity against self-antigens. Selective gene polymorphisms that regulate mitochondrial apoptosis in autoreactive B and T cells represent another key aspect in the induction of autoimmunity. Various mitochondrial abnormalities, including changes in mitochondrial function, oxidative stress, genetic polymorphism, mitochondrial DNA mutations, and apoptosis pathways, are each linked to different aspects of lupus pathogenesis. However, whether targeting these mitochondrial pathologies can be used to harness autoimmunity remains to be explored.

Lymph nodes (LNs) are the critical sites of immunity, and the stromal cells of LNs are crucial to their function. Our understanding of the stromal compartment of the LN has deepened recently with the characterization of nontraditional stromal cells. CD41 (integrin alphaIIb) is known to be expressed by platelets and hematolymphoid cells. We identified two distinct populations of CD41(+)Lyve1(+) and CD41(+)Lyve1(-) cells in the LNs. CD41(+)Lyve1(-) cells appear in the LN mostly at the later stages of the lives of mice. We identified CD41(+) cells in human LNs as well. We demonstrated that murine CD41(+) cells express mesodermal markers, such as Sca-1, CD105 and CD29, but lack platelet markers. We did not observe the presence of platelets around the HEVs or within proximity to fibroblastic reticular cells of the LN. Examination of thoracic duct lymph fluid showed the presence of CD41(+)Lyve1(-) cells, suggesting that these cells recirculate throughout the body. FTY720 reduced their trafficking to lymph fluid, suggesting that their egress is controlled by the S1P1 pathway. CD41(+)Lyve1(-) cells of the LNs were sensitive to radiation, suggestive of their replicative nature. Single cell RNA sequencing data showed that the CD41(+) cell population in naive mouse LNs expressed largely stromal cell markers. Further studies are required to examine more deeply the role of CD41(+) cells in the function of LNs.

Skin pigmentation has been linked to the development, prevalence, and severity of several immune-mediated diseases such as SLE. Here, we asked whether fibromodulin (FMOD), which is highly expressed in skin with light complexion, can explain the known differences in the magnitude of inflammation. C57 mice with different levels of pigmentation and FMOD were injected with human lupus serum to induce skin inflammation. Histopathologic studies revealed that black C57 FMOD+/+ that produce low levels of FMOD and white C57 FMOD -/- mice develop more severe inflammation compared with white FMOD +/+ mice. This study also revealed that dark pigmentation and FMOD deletion correlates with the increased numbers of Langerhans cells. Altogether, we identify low pigmentation and FMOD are linked to low severity of inflammation and approaches to promote FMOD expression should offer clinical benefit.