Allergic asthma is a chronic, inflammatory lung disease. Some forms of allergic asthma are characterized by Th2-driven eosinophilia while others are distinguished by Th17-driven neutrophilia. Stimulation of Toll-like receptor 4 (TLR4) on hematopoietic and airway epithelial cells (AECs) contributes to the inflammatory response to lipopolysaccharide (LPS) and allergens, but the specific contribution of TLR4 in these cell compartments to airway inflammatory responses remains poorly understood. We used novel, conditionally mutant Tlr4fl/fl mice to define the relative contributions of AEC and hematopoietic cell Tlr4 expression to LPS- and allergen-induced airway inflammation. We found that Tlr4 expression by hematopoietic cells is critical for neutrophilic airway inflammation following LPS exposure and for Th17-driven neutrophilic responses to the house dust mite (HDM) lysates and ovalbumin (OVA). Conversely, Tlr4 expression by AECs was found to be important for robust eosinophilic airway inflammation following sensitization and challenge with these same allergens. Thus, Tlr4 expression by hematopoietic and airway epithelial cells controls distinct arms of the immune response to inhaled allergens.

Key Points Genetic elimination of the coagulation transglutaminase fXIII limits arthritis incidence and severity in mice. FXIII supports arthritis pathogenesis through distinct mechanisms linked to joint inflammation and osteoclastogenesis.

Alterations in the gut microbiota have been proposed to modify the development and maintenance of obesity and its sequelae. Definition of underlying mechanisms has lagged, although the ability of commensal gut microbes to drive pathways involved in inflammation and metabolism has generated compelling, testable hypotheses. We studied C57BL/6 mice from two vendors that differ in their obesogenic response and in their colonization by specific members of the gut microbiota having well-described roles in regulating gut immune responses. We confirmed the presence of robust differences in weight gain in mice from these different vendors during high fat diet stress. However, neither specific, highly divergent members of the gut microbiota (Lactobacillus murinus, segmented filamentous bacteria) nor the horizontally transmissible gut microbiota were found to be responsible. Constitutive differences in locomotor activity were observed, however. These data underscore the importance of selecting appropriate controls in this widely used model of human obesity.

Objective A fundamental metric in the diagnosis of arthropathies is the pattern of joint involvement, including differences in proximal versus distal joints and patterns of symmetric or asymmetric disease. The basis for joint selectivity among arthritides and/or within a defined disease such as rheumatoid arthritis remains enigmatic. Coagulation and fibrinolytic activity are observed in both experimental animals with inflammatory joint disease and patients with inflammatory arthritis. However, the contribution of specific hemostatic factors to joint disease is not fully defined. We sought to determine the contribution of the fibrinolytic protease, plasminogen, to tumor necrosis factor α (TNFα)–driven arthritis in distinct joints in mice. Methods The impact of plasminogen and/or fibrinogen genetic deficiencies on arthritis progression was evaluated in Tg197 mice genetically predisposed to spontaneous, nonabating, and erosive polyarthritis due to exuberant human TNFα expression. Results Elimination of plasminogen in Tg197 mice significantly exacerbated the incidence and severity of arthritis within the paw joints, but simultaneously and dramatically diminished the entire spectrum of pathologies within the knee joints of the same animals. These opposing outcomes were both mechanistically linked to fibrin(ogen), in that superimposing fibrinogen deficiency reversed both the proarthritic phenotype in the paws and arthritis resistance in the knees of plasminogen-deficient mice. Intriguingly, the change in disease severity in the knees, but not the paws, was associated with a plasminogen-dependent reduction in matrix metalloproteinase 9 activity. Conclusion Plasminogen is a key molecular determinant of inflammatory joint disease capable of simultaneously driving or ameliorating arthritis pathogenesis in distinct anatomic locations in the same subject.

Rheumatoid arthritis (RA) is a common and debilitating autoimmune disease characterized by chronic inflammation, synovial hyperplasia, edema, cartilage and bone erosion and loss of joint function. Increasing evidence suggests that the plasminogen activation (PA) system plays a fundamental role in the mechanisms mediating inflammatory joint disease pathogenesis. However, analysis of the precise contribution of PA system components to arthritis pathogenesis has been complicated by the use of gene-targeted mice on non-susceptible genetic backgrounds or experimental models that simultaneously induce wound trauma in conjunction with arthritis induction. To rigorously define the contribution of the urokinase-type plasminogen activator system to arthritis pathogenesis, previously generated genetic deficiencies in both uPA and uPA receptor (uPAR) were inbred for 7 generations (99% inbred) to the well-characterized, collagen-induced arthritis (CIA)-susceptible strain, DBA/1J. Our results indicate a near complete amelioration of joint disease in uPA-deficient mice that was also observed in uPAR-deficient mice. Limited disease development in both uPA- and uPAR-deficient mice correlated with significantly reduced local mRNA levels of key inflammatory mediators (e.g., TNFα, IL-1β, and IL-6) in these animals. To determine if development of inflammatory joint disease in CIA-challenged mice was dependent on the expression of uPAR by non-hematopoietic- or hematopoietic-derived cells, reciprocal bone marrow transplant studies were performed. Mice in which uPAR deficiency was limited to the bone marrow compartment elicited significantly reduced macroscopic and histopathological disease in the paws and knees compared to wild-type mice or mice in which only hematopoietic-derived cells express uPAR. Our results are the first to report in the context of the highly CIA susceptible DBA/1 background that both uPA and uPAR are key determinants of inflammatory joint disease pathogenesis. Furthermore, our findings indicate a fundamental role for uPAR expression by hematopoietic cells in driving arthritis incidence and progression. Thus, these findings suggest that cell-surface associated uPA/uPAR-mediated proteolysis and/or uPAR-mediated signaling events from bone-marrow derived cells are important in promoting inflammatory joint disease, and that disrupting this key proteolytic/signaling system may provide a novel therapeutic strategy to limit clinical arthritis. Disclosures No relevant conflicts of interest to declare.