GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

Earley, Zachary M.; Lisicka, Wioletta; Sifakis, Joseph; Aguirre-Gamboa, Raúl; Kowalczyk, Anita; Barlow, Jacob T.; Shaw, Dustin G.; Discepolo, Valentina; Gona, Saideep; Ernest, Jordan D.; Matzinger, Polly; Barreiro, Luis B.; Morgun, Andrey; Bendelac, Albert; Ismagilov, Rustem F.; Shulzhenko, Natalia; Riesenfeld, Samantha J.; Jabrì, Bana

doi:10.1016/j.immuni.2022.12.009

Cited by 17 publications

(6 citation statements)

References 90 publications

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“…Overall, the crosstalk between immune and metabolic functions in the intestinal epithelium observed herein has a potential relevance for human physiology. Indeed, similar regulatory interactions have been observed in patients with common variable immunodeficiency, HIV enteropathy, and celiac disease 50 – 52 . Future studies would benefit from studying how IL-22RA1 signaling to additional metabolic organs, such as the pancreas, mediates obesity-associated disorders.…”

Section: Discussionsupporting

confidence: 59%

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders

Gaudino,

Singh,

Huang

et al. 2024

Nat Commun

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IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.

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Section: Discussionsupporting

confidence: 59%

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders

Gaudino,

Singh,

Huang

et al. 2024

Nat Commun

Self Cite

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“…To produce BCR monoclonal Ob -/- and Ob +/+ , the B6. MD4t transgenic mice, which carry a transgene for the rearranged heavy and light chains of a BCR recognizing hen egg lysozyme [ 50 ], were crossed to Ob -/- mice and subsequently to mice deficient for the IgH J segment locus (J H ) [ 51 ]. The resulting B6.…”

Section: Resultsmentioning

confidence: 99%

“…Ob -/- [ 80 ] mice on the C57BL6/J and BALB/cJ background, were from our laboratory collections. B6J.J H -/- mice [ 51 ] were a gift from Dr. Albert Bendelac (The University of Chicago). All animals were bred at the University of Chicago in a pathogen-free animal facility.…”

Section: Methodsmentioning

confidence: 99%

Deficiency in non-classical major histocompatibility class II-like molecule, H2-O confers protection against Staphylococcus aureus in mice

Cullum,

Perez-Betancourt,

Shi

et al. 2024

PLoS Pathog

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Staphylococcus aureus is a human-adapted pathogen that replicates by asymptomatically colonizing its host. S. aureus is also the causative agent of purulent skin and soft tissue infections as well as bloodstream infections that result in the metastatic seeding of abscess lesions in all organ tissues. Prolonged colonization, infection, disease relapse, and recurrence point to the versatile capacity of S. aureus to bypass innate and adaptive immune defenses as well as the notion that some hosts fail to generate protective immune responses. Here, we find a genetic trait that provides protection against this pathogen. Mice lacking functional H2-O, the equivalent of human HLA-DO, inoculated with a mouse-adapted strain of S. aureus, efficiently decolonize the pathogen. Further, these decolonized animals resist subsequent bloodstream challenge with methicillin-resistant S. aureus. A genetic approach demonstrates that T-cell dependent B cell responses are required to control S. aureus colonization and infection in H2-O-deficient mice. Reduced bacterial burdens in these animals correlate with increased titers and enhanced phagocytic activity of S. aureus-specific antibodies. H2-O negatively regulates the loading of high affinity peptides on major histocompatibility class II (MHC-II) molecules. Thus, we hypothesize that immune responses against S. aureus are derepressed in mice lacking H2-O because more high affinity peptides are presented by MHC-II. We speculate that loss-of-function HLA-DO alleles may similarly control S. aureus replication in humans.

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“…These symptoms are partly similar to tics. In addition, RA and its mediated signaling pathway are related to intestinal inflammation [ 56 ], and the changes in the RA pathway may be related to intestinal immune inflammation and microbial homeostasis imbalance [ 57 , 58 ]. Particular gut microbiota changes could be observed in children with TS [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating retinol and 25(OH)D contents and their association with symptoms in children with chronic tic disorders

Wang

Sun

et al. 2023

Eur Child Adolesc Psychiatry

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The present study measured serum levels of vitamin A (VA) and vitamin D (VD) in children with chronic tic disorders (CTD) and investigated their potential association with CTD and comorbidity of attention deficit hyperactivity disorder (ADHD) and the association of their co-insufficiencies or deficiencies with CTD symptoms. A total of 176 children (131 boys and 45 girls, median age of 9 years) with CTD were recruited as the CTD group. During the same period, 154 healthy children were selected as the healthy control (HC) cohort. Circulating retinol and 25-hydroxyvitamin D (25[OH]D) levels were measured for all participants using high-performance liquid chromatography (HPLC) and tandem mass spectrometry. The Yale Global Tic Severity Scale (YGTSS) was employed for the assessment of tic status and CTD impairment. The Swanson, Nolan, and Pelham Rating Scale (SNAP-IV) and the Children’s Yale-Brown Obsessive–Compulsive Scale (CY-BOCS) were used to evaluate comorbidity symptoms. CTD pediatric participants exhibited markedly diminished circulating retinol and 25(OH)D levels compared to HCs. Moreover, VA and VD deficiencies and their co-insufficiencies/deficiencies were more prevalent in CTD participants than HCs. Circulating 25(OH)D levels were inversely proportional to the YGTSS motor tic scores. YGTSS scores in CTD children with only VA or VD insufficiency or deficiency or with VA and VD co-insufficiency/deficiency did not differ from those in CTD children with normal VA and VD. CTD children with comorbid ADHD displayed reduced circulating retinol and 25(OH)D concentrations and elevated prevalence of VD deficiency compared to CTD participants without comorbid ADHD. Lower serum retinol content was intricately linked to the presence of elevated CTD and comorbid ADHD. VA and VD deficiencies and their co-insufficiencies/deficiencies were markedly enhanced in CTD pediatric participants compared to HCs. Lower VA concentration was linked to the presence of enhanced CTD and comorbid ADHD. Therefore, children with CTD, especially with comorbid ADHD, may be at a higher risk of VA or VD deficiency, which may prompt the clinicians to consider whether blood tests for VA and VD in CTD children would be helpful for clinical care.

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GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology

Cited by 17 publications

References 90 publications

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders

Deficiency in non-classical major histocompatibility class II-like molecule, H2-O confers protection against Staphylococcus aureus in mice

Circulating retinol and 25(OH)D contents and their association with symptoms in children with chronic tic disorders

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