Biology subjects

Paik, D.

Publications and source records attributed to Paik, D..

4 recordsLinked to original sources

bioRxiv2022

Methotrexate inhibition of muropeptide transporter SLC46A2 controls psoriatic skin inflammation

Cytosolic innate immune sensing is critical for protecting barrier tissues. NOD1 and NOD2 are cytosolic sensors of small peptidoglycan fragments (muropeptides) derived from the bacterial cell wall. These muropeptides enter cells, especially epithelial cells, through unclear mechanisms. We previously implicated SLC46 transporters in muropeptide transport in Drosophila immunity. Here we focus on Slc46a2, which is highly expressed in mammalian epidermal keratinocytes, and show that it is critical for delivery of DAP-muropeptides and activation of NOD1 in keratinocytes, while the related transporter Slc46a3 is critical for responding to MDP, the NOD2 ligand. In a mouse model, Slc46a2 and Nod1 deficiency strongly suppressed psoriatic inflammation, while methotrexate, a commonly used psoriasis therapeutic, inhibited Slc46a2-dependent transport of DAP-muropeptides. Collectively these studies define SLC46A2 as a transporter of NOD1 activating muropeptides, with critical roles in the skin barrier, and identify this transporter as an important target for anti-inflammatory intervention.

immunology↗

bioRxiv2021

Human gut bacteria produce TH17-modulating bile acid metabolites

The microbiota plays a pivotal role in gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17a (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. While it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown. Furthermore, it was not clear whether 3-oxoLCA and other immunomodulatory bile acids are associated with gut inflammatory pathologies in humans. Using a high-throughput screen, we identified human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Like 3-oxoLCA, isoLCA suppressed TH17 differentiation by inhibiting ROR{gamma}t (retinoic acid receptor-related orphan nuclear receptor {gamma}t), a key TH17 cell-promoting transcription factor. Levels of both 3-oxoLCA and isoLCA and the 3-hydroxysteroid dehydrogenase (3-HSDH) genes required for their biosynthesis were significantly reduced in patients with inflammatory bowel diseases (IBD). Moreover, levels of these bile acids were inversely correlated with expression of TH17 cell-associated genes. Overall, our data suggest that bacterially produced TH17 cell-inhibitory bile acids may reduce the risk of autoimmune and inflammatory disorders such as IBD.

immunology↗

bioRxiv2019

Gut-innervating nociceptor neurons protect against enteric infection by modulating the microbiota and Peyer’s patch microfold cells

Gut-innervating nociceptor sensory neurons respond to noxious/tissue-damaging stimuli by initiating protective responses and releasing mediators that regulate tissue inflammation, gastrointestinal secretion, and motility. The role of nociceptors in host defense against enteric pathogens is unclear. Here, we found that gut-extrinsic nociceptor neurons are critical in protecting the host against Salmonella typhimurium (STm) infection. Nociceptors responded to STm by releasing the neuropeptide calcitonin gene-related peptide (CGRP). Targeted depletion of Nav1.8 and TRPV1 neurons from gut-extrinsic dorsal root ganglia and vagal ganglia increased STm colonization, invasion, and dissemination. Nociceptors regulated the gut microbiota at homeostasis, specifically segmented filamentous bacteria (SFB) levels in the ileum, which protected against STm by colonization resistance. Nociceptors also regulated the density of microfold epithelial cells in the Peyers patch via CGRP to limit points of entry for STm invasion into host tissues. Understanding how host sensory neurons crosstalk with pathogenic bacteria may impact treatments for enteric infections.\n\nHIGHLIGHTSO_LINav1.8 and TRPV1 nociceptors defend against Salmonella typhimurium (STm) infection\nC_LIO_LINociceptors shape the gut microbiota and SFB levels which resist pathogen colonization\nC_LIO_LINociceptors suppress Peyers patch microfold cell density to limit pathogen invasion\nC_LIO_LINeurons sense STm and release CGRP to modulate microfold cells and host defense\nC_LI

immunology↗

bioRxiv2018

Bile acid metabolites control Th17 and Treg cell differentiation

Bile acids are abundantly present in the mammalian gut, where they undergo bacteria-mediated transformation, generating a large pool of bioactive molecules. While they have been shown to affect host metabolism, cancer progression and innate immunity, it is unknown whether bile acids affect the function of adaptive immune cells such as T cells expressing IL-17a (Th17 cells) and regulatory T cells (Tregs) that mediate inflammatory and anti-inflammatory responses, respectively. By screening a small-molecule library primarily composed of bile acid metabolites, we identified two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as specific regulators of Th17 and Treg cells. While 3-oxoLCA inhibited Th17 cell differentiation by directly binding to its key transcription factor ROR{gamma}t (retinoid-related orphan receptor {gamma} t), isoalloLCA enhanced differentiation of Tregs through mitochondrial-dependent metabolic changes, leading to an increased expression of Foxp3. IsoalloLCA-dependent Treg enhancement required an intronic Foxp3 enhancer, the conserved noncoding sequence 3 (CNS3), which acts as an epigenetic switch that confers a poised state to the Foxp3 promoter. Lastly, oral administration of 3-oxoLCA and isoalloLCA to mice led to reduced Th17 and increased Treg cell differentiation in the intestinal lamina propria. Altogether, our data suggest novel mechanisms by which bile acid metabolites control host immune responses by directly modulating the Th17 and Treg balance.

immunology↗