The IRE1α/XBP1 pathway sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease.

Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. Endoplasmic reticulum (ER) stress is linked to inflammatory bowel disease (IBD). Herein, we used cell culture, mouse models, and human specimens to examine if ER stress in ILC3s impacts IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24h-rhythmic expression pattern of the master ER stress response regulator, IRE1α/XBP1. Proinflammatory cytokine IL-23 selectively stimulated IRE1α/XBP1 in mouse ILC3s through mitochondrial reactive oxygen species (mtROS). IRE1α/XBP1 was activated in ILC3s of mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in Crohn's disease patients before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with response to treatment. We demonstrate that a non-canonical mtROS-IRE1α/XBP1 pathway augments cytokine production by ILC3s and identify XBP1s+ ILC3s as a potential biomarker for predicting response to anti-IL-23 therapies in IBD.

Pathogenesis of Perianal Fistulising Crohn's Disease: Current Knowledge, Gaps in Understanding, and Future Research Directions.

Fistulising perianal involvement is a common presentation of Crohn's disease. Perianal Crohn's disease dramatically impairs patients' social and sexual life and its management remains a critical challenge in field of inflammatory bowel disease. No medical therapy is specifically designed for the treatment of perianal Crohn's disease, largely due to the poorly understood pathophysiology. Limited evidence from preclinical and clinical studies suggests that the initiation, progression, and maintenance of Crohn's disease-associated perianal fistulas involves complex interactions between host, microbial, and environmental factors. This review intends to discuss the possible roles of genetic predisposition, mucosal immunity, and gut microbiome in perianal Crohn's disease, and considers how epithelial-to-mesenchymal transition may contribute to the pathogenesis. It also summarises recent advances on the development of animal models and new therapies for perianal Crohn's disease. At the end, we discussed future directions in basic, translational, and clinical research that may dramatically improve our understanding of perianal Crohn's disease and open avenues for novel therapeutic strategies with a multidisciplinary approach. Overall, this review aims to identify current gaps in understanding of perianal fistulising Crohn's disease and to explore future research priorities for this debilitating condition.

Ornithine decarboxylase supports ILC3 responses in infectious and autoimmune colitis through positive regulation of IL-22 transcription.

Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17 cells. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against Citrobacter rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that ILC3-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as exacerbates autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.

TREM2 drives microglia response to amyloid-ß via SYK-dependent and -independent pathways.

Genetic studies have highlighted microglia as pivotal in orchestrating Alzheimer's disease (AD). Microglia that adhere to Aß plaques acquire a transcriptional signature, "disease-associated microglia" (DAM), which largely emanates from the TREM2-DAP12 receptor complex that transmits intracellular signals through the protein tyrosine kinase SYK. The human TREM2R47H variant associated with high AD risk fails to activate microglia via SYK. We found that SYK-deficient microglia cannot encase Aß plaques, accelerating brain pathology and behavioral deficits. SYK deficiency impaired the PI3K-AKT-GSK-3ß-mTOR pathway, incapacitating anabolic support required for attaining the DAM profile. However, SYK-deficient microglia proliferated and advanced to an Apoe-expressing prodromal stage of DAM; this pathway relied on the adapter DAP10, which also binds TREM2. Thus, microglial responses to Aß involve non-redundant SYK- and DAP10-pathways. Systemic administration of an antibody against CLEC7A, a receptor that directly activates SYK, rescued microglia activation in mice expressing the TREM2R47H allele, unveiling new options for AD immunotherapy.

Obstructive uropathy associated with rheumatoid arthritis successfully treated with steroids and immunosuppressive therapy: A case report.

RATIONALE: Urinary obstruction are relatively rare complications of autoimmune diseases including systemic lupus erythematosus and systemic vasculitis. It has never been reported in rheumatoid arthritis (RA). PATIENT CONCERNS: We report a case of a female patient with seropositive RA who presented with gross hematuria associated with worsening joint symptoms, found to have acute kidney injury (AKI), bilateral hydronephrosis with bilateral renal pelvis, and ureteral wall thickening. Uroscopy with biopsy demonstrated inflammation without evidence of malignancy. DIAGNOSES: Rheumatoid arthritis related inflammation and obstruction of the urinary tract. INTERVENTIONS: Prednisone 50 mg daily (tapering began 1 month later), iguratimod 50 mg daily, and leflunomide 20 mg daily were prescribed. OUTCOMES: The patient responded well to steroids and immunosuppressive therapy with complete resolution of hematuria, renal injury, and hydronephrosis. LESSONS: Our case showed that RA might cause local inflammation involving the urinary tract which leads to obstruction and AKI.

Cellular Stress Responses and Gut Microbiota in Inflammatory Bowel Disease.

Progresses in the past two decades have greatly expanded our understanding of inflammatory bowel disease (IBD), an incurable disease with multifaceted and challenging clinical manifestations. The pathogenesis of IBD involves multiple processes on the cellular level, which include the stress response signaling such as endoplasmic reticulum (ER) stress, oxidative stress, and hypoxia. Under physiological conditions, the stress responses play key roles in cell survival, mucosal barrier integrity, and immunomodulation. However, they can also cause energy depletion, trigger cell death and tissue injury, promote inflammatory response, and drive the progression of clinical disease. In recent years, gut microflora has emerged as an essential pathogenic factor and therapeutic target for IBD. Altered compositional and metabolic profiles of gut microbiota, termed dysbiosis, are associated with IBD. Recent studies, although limited, have shed light on how ER stress, oxidative stress, and hypoxic stress interact with gut microorganisms, a potential source of stress in the microenvironment of gastrointestinal tract. Our knowledge of cellular stress responses in intestinal homeostasis as well as their cross-talks with gut microbiome will further our understanding of the pathogenesis of inflammatory bowel disease and probably open avenues for new therapies.

Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism.

Inositol-requiring 1 (IRE1)/X-box-binding protein 1 (XBP1)-mediated signalling represents the most conserved branch of the unfolded protein response. A series of recent studies reveal novel and potentially ancient roles for this pathway in the coordination of metabolic and immune responses.