Abstract
Lupus nephritis (LN) is a serious complication in patients with systemic lupus erythematous (SLE). Despite progress in immunosuppressive treatments in the past few decades, the development of chronic kidney disease (CKD) and disease relapse remain important hurdles in LN management. The presence of CKD and renal failure are robust predictors for mortality in SLE and LN patients, and can be prevented by both immunological and non-immunological measures. Renal relapse was associated with attrition of kidney function and cumulative drug toxicities, and hence preventing flares are important in LN management. Effective induction therapies are key to achieve disease control and preserve nephron mass, thereby confers huge impact on long-term kidney function and patient survival. The B cell repertoire are important immune-reactive cells that show pivotal pathogenic relevance in SLE and LN. Emerging evidence shows that B cell abnormalities are central to the pathogenesis of SLE and LN, and B cell signatures may serve as useful biomarkers for disease relapse. Manipulation of the B cell repertoire also presents a promising therapeutic approach for initial and maintenance treatments in LN. The application of artificial intelligence (AI) has also become a popular strategy to assess renal histology in LN patients and predict future relapse risk. Drug repurposing has been successful in advancing treatments in SLE and LN, and examples include the use of mycophenolate, calcineurin inhibitors, mTOR inhibitors. This talk will highlight the different aspects that can overcome major hurdles in LN care – ranging from clinical, basic/translational and AI data.

Abstract

Activated brown adipocytes coordinate local vascular responses during cold exposure. It remains unclear whether and how thermogenic activation of brown adipocytes signals to the vasculature to enhance blood supply. Here, we identify a novel pathway in which activated brown adipocytes expel mitochondria in the form of mitochondrial extracellular vesicles (mitoEVs). MitoEVs are different from mitochondrial derived vesicles (MDVs). These mitoEVs are taken up by tissue-resident macrophages via the Mertk receptor, triggering efferocytosis and promoting M2-like polarization.

Strikingly, during acute cold exposure, this efferocytotic process leads to pronounced prostaglandin E1 (PGE1) production by macrophages, which is essential for vasodilation in brown adipose tissue. Impaired efferocytosis does not affect intrinsic thermogenic capacity of brown adipocytes—as shown by lipid droplet depletion and elevated local temperature—but disrupts systemic heat dissipation due to failed vascular adaptation.

Together, our findings reveal a mitoEV–macrophage–vasculature axis by which brown adipocytes actively shape their microenvironment to support effective thermogenic function, highlighting a novel mechanism of intercellular communication in metabolic regulation.

Abstract

Host resistance to infection is determined by how well primed the innate immune system is to respond on first exposure to an invader. It is unclear, however, whether host naturally possesses mechanism that can prime the innate immune system against pathogens. Here, we described how autophagy inhibits innate immune priming prior to infection that would normally confer resistance to respiratory pathogens. Autophagy-regulated innate immune priming prepares the lung for early response to infection via reprogramming of inflammatory cells independently of either the microbiome or adaptive immunity.  In wild-type animals, priming is suppressed by autophagy in alveolar macrophages. Disabling autophagy in these innate immune cells allows swifter and more efficient innate immune clearance of Staphylococcus aureus while minimizing lung damage and inflammation in mice. Enhancing the primed state of innate immunity by blocking autophagy also protects mice against influenza A virus. Primed innate immunity is triggered by IL-1R/MyD88 signaling and suppressed by autophagy in alveolar macrophages. Meanwhile, we also found that autophagy in alveolar macrophages suppresses neutrophil recruitment and the formation of neutrophil myeloid derived suppressor cells during Mycobacterium tuberculosis (Mtb) infection to control the disease, suggesting a hypothesis that the ancient pathogen Mtb is the evolutionary pressure to have autophagy in alveolar macrophage. Together, these unpublished results shifted our understanding of the role of autophagy in inflammation and infection and shed light on the potential use of autophagy modulators in clinical medicine.

Abstract

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Induced pluripotent stem cells (iPSCs) directly generated from somatic tissue provide cell sources for disease modeling, drug development, and regenerative therapies. However, they are tumorigenic, and tedious to obtain, and aging features are irreversibly erased limiting their applications to model and revert late-onset diseases. To tackle this challenge, we have established an efficient method to reprogram skin and blood cells to induced neural stem cells (iNSC) using engineered pioneer transcription factors. iNSCs possess single-cell clonality, self-renew, and give rise to mature neuronal subtypes and glial cells. Using sensitive lineage reporters in mouse cells and time-course multi-omics analysis in human cells at single-cell resolution, we defined iNSC reprogramming roadmaps and showed that they bypass a pluripotent state. Methylation and gene expression analysis suggest that some aging-related signatures are retained during iNSC reprogramming. We have begun to generate iNSCs directly from ALS patients and will compare maturity and pathogenesis to isogenic control motorneurons that pass through an iPSC state. We aim to develop authentic next-generation stem cell models that could capture aging and the pathology of neurodegeneration in a dish to disentangle these diseases and test therapeutic modalities.

Abstract

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   The gut is the structure by which the body absorbs nutrients and defends against pathogens. Gut function is autonomously regulated by the enteric nervous system (ENS), which orchestrates intestinal motility to move food through the digestive tract and expel potential pathogens. The mucosal surfaces of the gut are exposed to large quantities of food proteins and colonized by at least a thousand species of commensal microorganisms that live in symbiosis with their host. However, this luminal antigenic information is essentially overlooked in the classic ENS paradigm, which mainly senses simple mechanical and chemical cues. Thus, how information on the complex composition of the luminal contents is transmitted to the ENS and drives adaptive changes in gut function remains largely unclear. We found that a population of choline acetyltransferase (ChAT)-expressing T cells resides in mouse gut. Most of these cells belonged to a population of Foxp3+ regulatory T cells that were induced by dietary antigens and microbiota and produced ACh. Further investigation demonstrated that these cholinergic T cells were closely associated with AChR-expressing IPAN nerve fibers in the gut mucosae. Engineered loss of Chat in T cells or Tregs resulted in impaired intestinal motility and decreased activity of enteric neurons. Based on our results, we propose a model in which cholinergic T cells are integrated into the enteric circuitry such that the immune system complements the nervous system in gathering and conveying the luminal content information necessary to regulate gut movement. A better understanding of this circuit may yield potential therapeutic targets for treating functional bowel disorders.