Category Archives: Innate immune cells

Macrophages Like IL-10 and DNA Methylation Regulates Tregs

This week on TIBDI, we see a plethora of interesting articles including a parallel publication about the necessity of IL-10 conditioning for gut macrophages and the ways that DNA methylation influences colon Treg proliferation.

IL10 Crystal Structure.rsh
IL-10 is an important conditioning factor for gut macrophages.
Intestinal Macrophages Need IL-10 Conditioning: Parallel Publication

Macrophages are an important immune cell of the intestines. For instance, CX3CR1hi macrophages capture antigens from the lumen by extending dendrites up through the epithelial layer and into the mucus to interact with passing bacteria. In the latest set of publications by the journal Immunity, parallel articles examine the relationship between macrophages and the anti-inflammatory cytokine interleukin (IL)-10. Using two different approaches, Dr. Ehud Zigmond of the Weizmann Institute of Science in Israel and Dr. Dror S. Shouval of Harvard Medical School in the United States were able to make similar conclusions.

Dr. Zigmond, using macrophage-restricted Il-10-/- and Il-10ra-/- mice, determined that macrophages with deficient IL-10 secretion were not nearly so harmful to the gut as macrophages not being able to respond to IL-10. Losing the ability to be conditioned by IL-10 made the macrophages more pro-inflammatory and led to spontaneous colitis. Dr. Shouval approached his research by creating bone-marrow chimeras with Rag2-/-Il-10rb-/- bone marrow and using the T cell transfer model of colitis. He found that loss of IL-10 signaling in innate immune cells led to colitis development. His work, unlike that of Dr. Zigmond, revealed that IL-10 conditioned macrophages are needed for proper regulatory T cell (Treg) development, and mucosal immune tolerance. He also found that pediatric inflammatory bowel disease (IBD) patients with mutations in their IL-10 receptors also had more pro-inflammatory macrophages. This work may lead to insights about why IBD develops.

Colonic Treg Proliferation Needs Uhrf1

Finding the ways that epigenetic mechanisms control T cell function and numbers is an exciting new field of research. One of the latest Nature Immunology articles adds fuel to the fire by publishing the work of Dr. Yuuki Obata of the University of Tokyo in Japan. She found that the DNA-methylation adaptor Uhrf1 was needed for Treg proliferation in the colon. This was determined by profiling genes activated in proliferating Treg after colonization with bacteria. This was then confirmed using T cell-specific Uhrf1-/- mice. Loss of Uhrf1 led to hypomethylation of a cell-cycle gene and a loss of Treg division in the colon. As a consequence of the low Treg numbers, Uhrf1-/- mice developed spontaneous colitis. It will be interesting to see if the same results can be found in the human setting.

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Notch for Oral Tolerance and Integrin Targeting in Crohn’s Disease

This week on TIBDI! Notch signaling is needed for the development of antigen sampling macrophages, and blocking integrins on T cells leads to less migration and colitis.

Macrophage
Notch signaling appears to be necessary for the development of cells that sample luminal antigens.
Notch and Intestinal Antigen Samplers

Recent literature has brought to light that macrophage-like cells expressing the chemokine receptor CX3CR1 and the integrin CD11c are needed to continually survey the antigen contents of the intestinal lumen. However, very little was known about how these cells develop. In a new publication, Dr. Chieko Ishifune of The University of Tokushima Graduate School in Japan shows that Notch signaling is involved. The Notch family is a highly conserved set up receptors designed for local cell communication, and they are involved in immune cell development. Using targeted knock-out mice, the researchers found that the downstream transcriptional regulator Rbpj was necessary for CD11c+CX3CR1+cells. Moreover, Notch1 and Notch2 were also needed. These results will help scientists learn more about oral tolerance, which could play a role in IBD.

Integrin Targeting Supported for Crohn’s Disease

The integrin α4 is suspected to be important for the recruitment of T cells to intestinal tissues. This concept is supported by the success of two blocking antibodies, Natalizumab and Vedolizumab, in Crohn’s disease (CD) clinical trials. To precisely examine the role of integrins on T cells during colitis, Dr. Elvira Kurmaeva of Louisiana State University Health Sciences Center transferred CD4+ T cells with a targeted deletion of α4 or β1 to induce colitis in immunodeficient mice. Her results indicated that loss of α4β7 lowered colitis severity. Further analysis of the colons showed that the mice had lower amounts of infiltrating CD4+ T cells, which matched results found in CD patients treated with Natalizumab. Interestingly, the migration problems were only apparent during inflammation, and didn’t affect T cell polarization.

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The Crohn’s Disease Gender Bias and Neutrophils Disrupt the Gut

Neutrophils
Neutrophils (with purple irregular nuclei) can shed proteins that disrupt the intestinal barrier.
This week on TIBDI! Neutrophils shed a protein that disrupts the intestinal barrier, hormones and T cells are behind Crohn’s disease gender skewing, and CD31 is the newest way to make dendritic cells anti-inflammatory.

Neutrophils Bust Up the Intestinal Barrier

During inflammatory bowel disease (IBD), neutrophils gather at sites of inflammation and often migrate through the intestinal epithelial barrier. A new model described by Dr. Dominique A. Weber and Dr. Ronen Sumagin now shows how dangerous this behavior is for intestinal wound healing. They found that neutrophils shed junctional adhesion molecule-like protein (JAML) during epithelial transmigration. JAML binds to a receptor found on epithelial cells called coxsackie-adenovirus receptor (CAR), and JAML and CAR interactions cause epithelial barriers to become leaky. While this leakiness may be needed for initial efficient immune cell infiltration, shed JAML prevents the barrier from regaining normal function and stops wound closure. Experiments showed that blocking JAML-CAR interactions could lead to accelerated wound repair. This discovery could help treat IBD-induced intestinal ulcerations.

Why Crohn’s Disease Prefers Women

There is a general acceptance that the prevalence of Crohn’s disease (CD) is higher in women than in men. W.A. Goodman and R.R. Garg of Case Western Reserve University School of Medicine suspected that this gender bias might be the same in spontaneous models of CD. This is, indeed, the situation. Female SAMP1/YitFc (SAMP) mice were more predisposed to spontaneous CD and had impaired regulatory T cells with low frequencies as compared to the male SAMP mice. An investigation of the T cells revealed that male SAMP T cells responded much differently than female SAMP T cells to estrogen signals. While the male T cells responded by increasing immunosuppressive functions and expanding regulatory T cells, the female cells were resistant to these signals. Finding ways to make female T cells sensitive to estrogen signals could decrease female susceptibility to CD.

More Ways to Induce Anti-inflammatory Dendritic Cells

CD31 is expressed on many types of immune cells and endothelial cells, and it is mainly seen as an adhesion and migration molecule. Recent evidence has shown that it also has inhibitory function on T cells, which means that it might have inhibitory functions in other cells. Marc Clement of the French National Institute of Health and Medical Research (INSERM) has now found that this is, indeed, the situation with dendritic cells (DCs). Signaling via CD31 prevented DC maturation, migration and reduced pro-inflammatory signaling cascades. CD31-stimulated DC also preferentially polarized T cells towards a regulatory phenotype, and transfer of these DCs to a rodent model of multiple sclerosis delayed disease development. These results suggest that CD31 may also be potentially interesting for IBD.

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X-linked and Autophagy Genes Support Crohn’s Disease Development

Caspase 3 subunits
Caspase-3 is the missing link between an autophagy gene mutation and heightened inflammation.
This week on TIBDI: Impressive results in Nature show how gene mutations cause reduced autophagy, and mutations in the XIAP gene lead to early-onset CD in male patients.

From an Autophagy Gene to Crohn’s Disease

Genome wide association scans confirmed the importance of ATG16L1 mutations in Crohn’s disease (CD), especially a variant consisting of an Alanine to Threonine exchange at the 300th amino acid. Despite an abundance of literature, the precise mechanism linking the mutation to reduced autophagy was unknown. Dr. Aditya Murthy from Genentech, Inc. has now found an answer. The mutation is located in a cleavage site for the enzyme caspase-3, and it makes the protein more susceptible to cleavage. Caspase-3 is well known for its role in initiating apoptosis during cellular trauma, for instance during metabolic stress or intestinal infection. Without proper autophagy, macrophages are unable to neither regulate their energy consumption nor properly eliminate pathogens, and have an heightened inflammatory response.

XIAP Mutations in Early Onset CD

Variants in the gene encoding for the X-linked inhibitor of apoptosis protein (XIAP) can sometimes lead to intestinal inflammation. XIAP is involved with a multitude of processes including NOD signaling, apoptosis and NKT cell development. To investigate XIAP’s possible role in CD, Dr. Yvonne Zeissig and her colleagues at the University Medical Center Schleswig-Holstein in Germany, looked at CD patient samples to find if there were clear associations between XIAP and immune cell function. She found that approximately 4% of male early-onset CD patients had unique mutations in their XIAP genes. Experiments with patient primary cells revealed that loss of XIAP function caused defects in NOD1/2 signaling.

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The Dark Side of Retinoic Acid and Interleukin-22

Salmonella species growing on XLD agar - Showing H2S production
IL-22 secretion during intestinal inflammation gives Salmonella a competitive advantage.
This week on TIBDI: Th1 cells can activate macrophages with innate signals alone, retinoic acid is no hero in Crohn’s disease, and interleukin-22 allows some pathogens to thrive.

TCRs Are Not Always Needed

Macrophages and T cells play are important in inflammatory bowel disease (IBD). Learning about how these cells interact could lead to more insight about how IBD progresses. Hope O’Donnell of the University of Minnesota has now gleaned new insights about their interactions. She looked into the mechanisms behind non-cognate stimulation of Th1 cells (non-TCR stimulation) and their ability to secrete macrophage-activating IFNγ. Using genetically manipulated mice and a Salmonella infection model, her results show that Th1 (and CD8+) cells produce plenty of IFNγ as long as they are exposed to Toll-like receptor ligands and products of activated inflammasomes like interleukin (IL)-18 and IL-33. This study underscores the flexibility and strength of the adaptive immune response.

The Pitfalls of Retinoic Acid

Retinoic acid is the current darling of those studying anti-inflammatory responses as it has been shown that retinoic acid can lead to regulatory T cell development. To determine if retinoic acid was actually lowered during Crohn’s disease (CD), Dr. Theodore J. Sanders of the Blizard Institute in London measured retinaldehyde dehydrogenase (RALDH) activity in cell samples collected from CD patients and controls. In all of the dendritic cells and macrophages tested, the RALDH activity (ability to produce retinoic acid) was increased in CD patients compared to controls. Surprisingly, blocking retinoic acid signaling actually decreased the ability of monocytes to differentiate into TNFα-producing macrophages in in vitro tests. This would suggest that retinoic acid is less helpful in CD than what one would expect.

Salmonella Exploits Interleukin-22

Interleukin-22 is a cytokine that is designed to boost immune defenses at the gut-lumen interface. It induces antimicrobial peptide release along with factors that sequester essential metal ions (like iron) that bacteria need to grow. Dr. Judith Behnsen of the University of California has now discovered that these processes can be exploited by certain pathogens, like Salmonella. She found that IL-22 deficient mice were much less susceptible to Salmonella overgrowth. The reason was that Salmonella has the ability to compensate for the loss of ambient metal ions, while this is not the situation for many commensals. This allows Salmonella to create for a rather large niche for itself, while IL-22-induced processes decimate the competition.

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