Immune Complexes Inhibit IL-1 Secretion and Inflammasome Activation

Abstract

Immunoglobulin G (IgG) immune complexes have been shown to modify immune responses driven by antigen presenting cells in either a pro- or anti-inflammatory direction depending upon the context of stimulation. However, the ability of immune complexes to modulate the inflammasome-dependent innate immune response is unknown. Here we show that IgG immune complexes suppress IL-1α and IL-1β secretion through inhibition of inflammasome activation. The mechanism by which this inhibition occurs is via immune complex ligation of activating Fcγ receptors (FcγR), resulting in prevention of both activation and assembly of the inflammasome complex in response to NLRP3, NLRC4, or AIM2 agonists. In vivo, administration of antigen in the form of an immune complex during priming of the immune response inhibited resultant adaptive immune responses in a NLRP3 dependent model of allergic airway disease. Our data reveal an unexpected mechanism regulating CD4+ T cell differentiation, whereby immune complexes suppress inflammasome activation and the generation of IL-1α and IL-1β from antigen presenting cells, which are critical for the antigen-driven differentiation of CD4+ T cells.

Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection

“…Another recent study indicated that immune complexes inhibit inflammasome activation (90). However, in the study by Janczy et al (90), immune complexes interfered with inflammasome assembly induced by a separate priming signal.…”

“…However, in the study by Janczy et al (90), immune complexes interfered with inflammasome assembly induced by a separate priming signal. In the current study, DENV alone or DENV immune complexes were the sole stimulus.…”

Host‐ and pathogen‐derived adjuvant coatings on protein nanoparticle vaccines

“…Antibodies have been proposed as host‐derived adjuvants before . Most of these studies have been with soluble immune complexes consisting of soluble antigen bound to a cognate antibody . This strategy targets the antigen to Fc receptor‐bearing antigen presenting cells, yet does not exploit a second feature of antibody‐mediated adjuvancy—the activation of complement.…”

A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity

“…Ig (IVIG) is a marketed product composed of Igs from thousands of human donors (1). While the mechanism by which IVIG restores functional humoral immunity in patients with antibody deficiencies are self-evident, the mechanisms by which IVIG regulates tolerance in patients with autoimmune disease are much more speculative (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The practical consequence of such mechanistic diversity and/or uncertainty has been the historic inability to develop a recombinant drug that is capable of recapitulating the antiinflammatory properties of IVIG.…”