Wen Zhang

Loss of SHARPIN, a component of the linear ubiquitin chain assembly complex (LUBAC), causes systemic inflammation including the accumulation of eosinophils across multiple tissues in mice. However, the mechanisms by which SHARPIN regulates type 2 inflammation remain unclear. Here, we found that SHARPIN deficiency resulted in increased numbers of type 2 innate lymphoid cells (ILC2s) in the lung and other tissues via a cell-extrinsic mechanism. SHARPIN loss enhanced interleukin-33 (IL-33) production by lung stromal cells in vivo and in vitro, thereby promoting ILC2 proliferation. Mechanistically, SHARPIN directly bound IL-33 through its Pleckstrin homology-linker region and restrained IL-33 release independently of its ubiquitination. Combined deficiency of SHARPIN and IL-33 completely reversed ILC2 increase and lung inflammation, but not stromal cell death. Our study reveals a non-canonical, ubiquitin-independent function of SHARPIN as a gatekeeper of IL-33-driven type 2 inflammation.

Type 2 immunity has evolved to protect against worms but becomes harmful when activated during allergic inflammation. Group 2 innate lymphoid cells (ILC2s) drive type 2 responses by rapidly secreting IL-5 and IL-13. The alarmins, IL-25, IL-33, and TSLP activate ILC2s and are linked to allergic diseases. However, how alarmins connect to the transcriptional networks driving type 2 effector functions remains elusive. Here, we performed RNA sequencing of ILC2s deficient in IL-25, IL-33, or TSLP pathway and identified the transcription factor Blimp-1 as an IL-33–regulated gene in ILC2s. While Blimp-1 was dispensable for ILC2 development, this transcription factor was required for type 2 cytokine production, driving eosinophilia or promoting worm expulsion. Blimp-1 deficiency resulted in reduced IRF4 expression, while Irf4-deficient ILC2s showed diminished Blimp-1 and IL-33 receptor expression, revealing a reciprocal Blimp-1–IRF4 circuit downstream of the IL-33 receptor. These findings expose the Blimp-1–IRF4 axis as an alarmin-regulated transcriptional network controlling ILC2 effector functions required for type 2 immunity.

Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation, or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon, which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in the accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, the inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared with controls, implicating this diet–microbiota–ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber–induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases.

Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory, and malignant diseases ^1–8 . Here, we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that are specific for the microbiota and express the transcription factor RORγt. We profiled all RORγt ⁺ immune cells at single cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of Tregs and lymphoid tissue-induced (LTi)-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s have interconverting potential with RORγt ⁺ extrathymic Aire-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt ⁺ Tregs and prevent their expansion as inflammatory T helper (Th)17 cells. This occurs through ILC3-mediated antigen-presentation, interleukin-2 gradients, and α v integrin. Finally, single-cell analyses demonstrate that ILC3 and RORγt ⁺ Treg interactions are impaired in inflammatory bowel disease. Our results define a novel paradigm whereby ILC3s positively select for antigen specific RORγt ⁺ Tregs, and against Th17 cells, to establish immune tolerance to the microbiota and intestinal health.

Group 2 innate lymphoid cells (ILC2s) reside in multiple tissues, including lymphoid organs and barrier surfaces, and secrete type 2 cytokines including interleukin-5 (IL-5), IL-9, and IL-13. These cells participate in multiple physiological processes including allergic inflammation, tissue repair, metabolic homeostasis, and host defense against helminth infections. Recent studies indicate that neurotransmitters and neuropeptides can play an important role in regulating ILC2 responses; however, the mechanisms that underlie these processes in vivo remain incompletely defined. Here, we identify that activated ILC2s up-regulate choline acetyltransferase (ChAT)—the enzyme responsible for the biosynthesis of acetylcholine (ACh)—after infection with the helminth parasite Nippostrongylus brasiliensis or treatment with alarmins or cytokines including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). ILC2s also express acetylcholine receptors (AChRs), and ACh administration promotes ILC2 cytokine production and elicits expulsion of helminth infection. In accordance with this, ChAT deficiency in ILC2s leads to defective ILC2 responses and impaired immunity against helminth infection. Together, these results reveal a previously unrecognized role of the ChAT-ACh pathway in promoting type 2 innate immunity to helminth infection.

In recent years there have been excellent results in attitude estimation techniques, which aim to offer precise posture information for various industrial robots. Various tasks especially the inspections and welding on the eroded surface of large-scale hydraulic turbine blade are performed by mobile robots. In those case, the robot moves on curved surfaces along the predetermined route and it is necessary to know its real-time attitude angle for the welding task. In this paper, we propose a novel approach for improving the accuracy of attitude estimation of all-position welding robot using low-cost MEMS inertial sensors. The gyro drift error caused by temperature or bias instability is estimated when the welding robot is at zero velocity in the whole course of navigation. The performance of the proposed approach will be analyzed through a series of experiments by the all-position welding robot developed in our laboratory. To show the performance of the presented method, the experimental results obtained by a low-cost Inertial measurement unit (IMU) and a high-accuracy IMU were compared.

Metabolic pathways such as glycolysis or oxidative phosphorylation play a key role in regulating macrophage function during inflammation and tissue repair. However, how exactly the VHL–HIF–glycolysis axis is involved in the function of tissue-resident macrophages remains unclear. Here we demonstrate that loss of VHL in myeloid cells resulted in attenuated pulmonary type 2 and fibrotic responses, accompanied by reduced eosinophil infiltration, decreased IL-5 and IL-13 concentrations, and ameliorated fiber deposition upon challenge. VHL deficiency uplifted glycolytic metabolism, decreased respiratory capacity, and reduced osteopontin expression in alveolar macrophages, which impaired the function of type 2 innate lymphoid cells but was significantly reversed by HIF1α inhibition or ablation. The up-regulated glycolysis altered the epigenetic modification of osteopontin gene, with the metabolic intermediate 3-phosphoglyceric acid as a key checkpoint controller. Thus, our results indicate that VHL acts as a crucial regulatory factor in lung inflammation and fibrosis by regulating alveolar macrophages.