Monosodium uric acid (MSU) crystal, the etiological agent of gout, has been shown to trigger innate immune responses via multiple pathways. It is known that MSU-induced lipid sorting on plasma membrane promotes the phosphorylation of Syk and eventually leads to the activation of phagocytes. However, whether this membrane lipid-centric mechanism is regulated by other processes is unclear. Previous studies showed that Clec12a, a member of the C-type lectin receptor family, is reported to recognize MSU and suppresses this crystalline structure-induced immune activation. How this scenario is integrated into the lipid sorting-mediated inflammatory responses by MSU, and particularly, how Clec12a intercepts lipid raft-originated signaling cascade remains to be elucidated. Here, we found that the ITIM motif of Clec12a is dispensable for its inhibition of MSU-mediated signaling; instead, the transmembrane domain of Clec12a disrupts MSU-induced lipid raft recruitment and thus attenuates downstream signals. Single amino acid mutagenesis study showed the critical role of phenylalanine in the transmembrane region for the interactions between C-type lectin receptors and lipid rafts, which is critical for the regulation of MSU-mediated lipid sorting and phagocyte activation. Overall, our study provides new insights for the molecular mechanisms of solid particle-induced immune activation and may lead to new strategies in inflammation control.
© 2023 Xu et al.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.