An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma

Abstract

Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic inflammation.

Caspase-1: an integral regulator of innate immunity

“…Activated caspase-1 dampens IL-33 mRNA expression and IL-33 protein levels in the lungs, thereby regulating the HDM-induced allergic response [37]. Furthermore, absence of caspase-1 was associated with increased expression of uric acid and spleen tyrosine kinase, both known to be involved in the induction of type-2 immunity [37,73]. Blockade of IL-33 signaling reduced the development of Th2 immunity following HDM immunization in caspase-1 knockout mice, emphasizing IL-33 as main target for the NLRP3/caspase-1-mediated regulation of HDMinduced experimental allergic airway inflammation.…”

Death at the airway epithelium in asthma

“…In a house dust mite (HDM)-driven murine model of asthma, the epithelial repair factor Trefoil factor 2 (TFF-2) was shown to induce IL-33 production in airway epithelia, alveolar macrophages and FcεRI + inflammatory DCs and thus contribute to induction of Th2 immunity [8]. Other alarmins like HM-GB1, uric acid and ATP that are typically released in response to necrotic cell death, also seem to be released at an increased rate in asthmatic airways, but again it is unclear whether they are released from dying cells or by an active process [9].…”

Epithelial Cell Regulation of Immune Responses in the Lung

“…It is still unclear if the inflammasomecaspase1-IL-1β axis is involved in asthma development. In our own work using HDM sensitization via inhalation, there was no reduction in asthma development in mice lacking the key inflammasome components Nlrp3, Asc, or caspase-1 (Kool et al, 2011). In models of skin sensitization to HDM, there appears, however, to be a role for the Nlrp3 inflammasome (Allen et al, 2012).…”