Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10

Rojas, Olga L.; Pröbstel, Anne-Katrin; Porfilio, Elisa A.; Wang, Angela A.; Charabati, Marc; Sun, Tian; Lee, Dennis S. W.; Galicia, Georgina; Ramaglia, Valeria; Ward, Lesley A.; Leung, Leslie Y. T.; Najafi, Ghazal; Khaleghi, Khashayar; Garcillán, Beatriz; Li, Angela; Besla, Rickvinder; Naouar, Ikbel; Cao, Eric; Chiaranunt, Pailin; Burrows, Kyle; Robinson, Hannah G; Allanach, Jessica R.; Yam, Jennifer; Luck, Helen; Campbell, Daniel; Allman, David; Brooks, David G.; Tomura, Michio; Baumann, Ryan; Zamvil, Scott S.; Bar‐Or, Amit; Horwitz, Marc S.; Winer, Daniel A.; Mortha, Arthur; Mackay, Fabienne; Prat, Alexandre; Osborne, Lisa C.; Robbins, Clinton S.; Baranzini, Sergio E.; Gommerman, Jennifer L.

doi:10.1016/j.cell.2018.11.035

Cited by 274 publications

(165 citation statements)

References 50 publications

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“…To this end, a recent study showed that serum IgA from individuals with T1D has a differential ability to bind specific bacteria compared with that from healthy controls (25). Furthermore, IL-10 production from recirculating intestinal IgA + B cells protected mice from developing autoimmune encephalomyelitis (26). Thus, both IgA + B cells and secreted IgA have important roles in mediating gut homeostasis and the susceptibility to autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Gut microbial metabolites alter IgA immunity in type 1 diabetes

Hao¹,

Pearson²,

Peng³

et al. 2020

JCI Insight

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Section: Introductionmentioning

confidence: 99%

Gut microbial metabolites alter IgA immunity in type 1 diabetes

Hao¹,

Pearson²,

Peng³

et al. 2020

JCI Insight

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“…Analysis of publicly available ChIP-seq datasets in both murine and human B cells are in line with this finding, suggesting that IL-10 is a significantly enriched target of BLIMP1 32,45 . This observation is reminiscent of recent 305 work highlighting the role for BLIMP1-expressing regulatory plasmablasts and plasma cells in vivo 3,4,46,47 , but also in humans ex vivo 47 . Whilst this previous work provided a correlative link between BLIMP1 and IL-10, we suggest that BLIMP1 is a direct regulator of IL-10 in B cells.…”

mentioning

confidence: 61%

“…Immunosuppressive B cells form a critical component of the immune regulatory compartment 1,2 . It is thought that their suppressive capacity derives mainly from their ability to produce IL-10, and in the absence of any lineage marker, this is considered a hallmark of regulatory B cells [3][4][5][6] . Their functional importance has been well described in murine models of disease, demonstrating a potent regulatory capacity across a number of contexts including infection, cancer, and autoimmune disease 3,[7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Cholesterol metabolism drives regulatory B cell function

Bibby

Purvis

Hayday

et al. 2020

Preprint

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Regulatory B cells restrict immune and inflammatory responses across a number of contexts. Thiscapacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven 25 by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) was required to specifically drive IL-10 production, and to attenuate Th1 responses.Furthermore, GGPP-dependent protein modifications controlled signaling through PI3Kd-AKT-GSK3, which in turn promoted BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome, termed mevalonate kinase 30 deficiency (MKD). Consistent with our findings, B cells from MKD patients induced poor IL-10 responses and were functionally impaired. Moreover, metabolic supplementation with GGPP was able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells. 40Comparable suppressive activity has been demonstrated in human regulatory B cells in vitro, suggesting that these cells also contribute toward regulating inflammatory responses in humans 5,6 . In support of this, IL-10 producing B cells have been demonstrated to be numerically depleted or functional impaired, ex vivo, in patients with inflammatory disease 5,11,12 . 45Despite the importance of IL-10 production by B cells, relatively little is known about the molecular mechanisms that govern its expression. Typically, induction of a regulatory phenotype in both human and murine B cells has been achieved through ligation of TLR9 or CD40 5,6,13 . Downstream, PI3K and ERK signals appear to be important for IL-10 expression 14,15 . This is in broad agreement with in vivo data from mouse models suggesting that both TLR and CD40 signals are required for the induction of 50 IL-10 in response to inflammatory stimuli 3,13 . However, precise details of the signaling cascades or cellular profiles underpinning the induction of a regulatory program in B cells are poorly understood.Control of immune cell metabolism is critical in regulating fundamental immunological processes 16,17 . However, in comparison to innate cell and T cell lineages, there has been relatively little work 55 aimed at understanding the metabolic regulation of B cell biology [18][19][20] . Furthermore, there is currently no understanding toward the metabolic requirements of regulatory B cells. An emerging concept from studies of regulatory T cells and M2 macrophages is their heightened reliance on lipid metabolism in comparison to the metabolic requirements of inflammatory immune cell lineages. Much of this work has focused on fatty acid oxidation, defining this as a central pathway that underpins polarization and 60 effector functions in regulatory cells 21 . In contrast, the contribution of cholesterol metabolism (the multi-step conversion of HM...

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“…Additionally, an underrepresentation of Lachnospiraceae at the family level and Bifidobacterium and Lactobacillus at the genus level has been described in depressed cohorts (Naseribafrouei et al, 2014;Jiang et al, 2015;Aizawa et al, 2016). Interestingly, probiotics are effective in reducing depressive symptoms and microbiome transfers from depressed human patients into rats were sufficient to induce depressive-like behaviors in the animals, further supporting the idea that the microbiome can initiate depression (Kelly et al, 2016;Rojas et al, 2019). However, gaps remain in our understanding of how the gut-brain axis contributes to depression.…”

Section: The Gut-brain Axis In Depressionmentioning

confidence: 96%

The Role of Gut Mucins in the Etiology of Depression

Rivet-Noor¹,

Gaultier²

2020

Front. Behav. Neurosci.

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Major depressive disorders are global health problems that affect more than 6% of the U.S. population. Despite years of research, the etiology of depression remains unclear. Historically, it was believed that depression started within the central nervous system (CNS), but alternative hypotheses have recently challenged this dogma. Indeed, experimental and clinical evidence show that the gut microbiome could be an active player in depression initiation. The composition of bacterial species in depressed patients is significantly different from control microbiomes, and the transfer of the microbiome from depressed patients is sufficient to initiate depressive symptoms in animals. Additionally, the gut microbiome is known to change in the presence of depression risk factors such as chronic stress. While there is strong evidence delineating a role for microbial dysbiosis in depression, the initiating event for this dysbiosis remains unknown. Within the gut, microbiota reside in the mucus layer, a critical gel-like barrier involved in protecting the host from unwanted pathogen interactions, as well as regulating the immune system. Though the mucus layer is often ignored in the face of dysbiosis, it represents a dynamic and important piece of host machinery that has the potential to impact a wide variety of biological processes. Here, we review evidence supporting the novel concept that stress can modify the delicate mucus-microbiome balance, initiating dysbiosis, and ultimately leading to depression.

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Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10

Cited by 274 publications

References 50 publications

Gut microbial metabolites alter IgA immunity in type 1 diabetes

Gut microbial metabolites alter IgA immunity in type 1 diabetes

Cholesterol metabolism drives regulatory B cell function

The Role of Gut Mucins in the Etiology of Depression

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