Inflammasomes continue to generate interest in an increasing number of disciplines owing to their unique ability to integrate a myriad of signals from pathogen- and damage-associated molecular patterns into a proinflammatory response. This potent caspase-1–dependent process is capable of activating the innate immune system, initiating pyroptosis (an inflammatory form of programmed cell death), and shaping adaptive immunity. The NLRP3 inflammasome is the most thoroughly studied of the inflammasome complexes that have been described thus far, perhaps owing to its disparate assortment of agonists. This review will highlight our current understanding of the mechanisms of both priming and activation of the NLRP3 inflammasome.

Objective: Arthritis and valvular carditis co-exist in several human rheumatic diseases, including systemic lupus erythematosus, rheumatic fever, and rheumatoid arthritis. K/BxN T-cell receptor transgenic mice develop spontaneous, autoantibody-associated arthritis and valvular carditis. The common Fc receptor gamma signaling chain (FcRγ) is required for carditis in K/BxN mice. FcRγ pairs with numerous receptors in a variety of cells. Here we sought to identify the FcRγ-associated receptors and FcγR-expressing cells that mediate valvular carditis in this model. Methods: We bred K/BxN mice lacking the genes encoding the activating Fc gamma receptors (FcγRI, III, and IV) and assessed for valvular carditis. We similarly assessed complement component C3-deficient K/BxN mice. Immunohistochemistry, bone marrow transplantation, and macrophage depletion were used to define the key FcRγ-expressing cell type. Results: Genetic deficiency of only one of the activating FcγRs did not prevent carditis, whereas deficiency of all three activating FcγRs did. Further analysis demonstrated that FcγRIII and FcγRIV were the key drivers of valve inflammation; FcγRI was dispensable. C3 was not required. FcRγ expression by radioresistant cells was critical for valvular carditis to develop, and further analysis pointed to macrophages as the key candidate FcγR-expressing effectors of carditis. Conclusion: FcγRIII and FcγRIV acted redundantly to promote valvular carditis in the K/BxN mouse model of systemic autoantibody-associated arthritis. Macrophage depletion reduced the severity of valve inflammation. These findings suggest that pathogenic autoantibodies engage FcγRs on macrophages to drive valvular carditis and provide new insight into the pathogenesis of cardiovascular inflammation in the setting of autoantibody-associated chronic inflammatory diseases.

IntroductionThe effector functions of immunoglobulin G (IgG) are mediated by interaction of its Fc region with Fc receptors (FcγRs) and/or the complement system. The three main pathways of complement activation converge at C3. However, C3-independent pathways can activate C5 and other downstream complement components during IgG-initiated inflammatory responses. These C3-independent pathways of C5 activation are triggered by activating FcγRs in some systems or can be activated by factors of the coagulation cascade such as thrombin. Here we studied the interplay of C3, C5, and activating FcγRs in a model of spontaneous autoantibody-driven arthritis.MethodsWe utilized the K/BxN TCR transgenic mouse model of arthritis. We bred K/BxN mice bearing targeted or naturally-occurring mutations in one or more of the genes encoding complement components C3, C5, and FcRγ, the cytoplasmic signaling chain shared by the activating FcγRs. We measured arthritis development, the production of arthritogenic autoantibodies, T cell activation status and cytokine synthesis. In addition, we treated mice with anti-C5 monoclonal antibodies or with the thrombin inhibitor argatroban.ResultsWe have previously shown that genetic deficiency of C5 protects K/BxN mice from the development of arthritis. We found here that C3-deficient K/BxN mice developed arthritis equivalent in severity to C3-sufficient animals. Arthritis also developed normally in K/BxN mice lacking both C3 and FcRγ, but could be ameliorated in these animals by treatment with anti-C5 monoclonal antibody or by treatment with argatroban. Production of arthritogenic autoantibodies, T cell activation, and T cell cytokine production were not affected by the absence of C3, C5, and/or FcRγ.ConclusionsIn K/BxN mice, C5-dependent autoantibody-driven arthritis can occur in the genetic absence of both complement C3 and activating FcγRs. Our findings suggest that in this setting, thrombin activates C5 to provoke arthritis.