Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

Redhu, Naresh Singh; Bakthavatchalu, Vasudevan; Conaway, Evan; Shouval, Dror S.; Tsou, Amy M.; Goettel, Jeremy A.; Biswas, Amlan; Wang, Chuanwu; Field, Michael; Müller, Werner; Bleich, André; Li, Ning; Gerber, Georg K.; Bry, Lynn; Fox, James G.; Snapper, Scott B.; Horwitz, Bruce H.

doi:10.7554/elife.27652

Cited by 29 publications

(53 citation statements)

References 55 publications

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“…Of note, GO analysis to detect potential upstream regulators of Runx3 Δ RM DEGs highlighted IL10RA and IFNG as the most significant regulators, with IL10RA having a negative z-score and IFNG a positive z-score ( Figure 5C). Conditional deletion of Il10ra in MNP (Cx3cr1-IL10ra Δ ) (Zigmond et al, 2014) and Il10rb -/mice (Redhu et al, 2017;Zigmond et al, 2014) develop spontaneous colitis, similar to that observed in Runx3 Δ mice. To examine a possible relationship between Runx3 and Il10 signaling in RM, we cross analyzed Runx3 Δ DEGs with the transcriptional profile of Il10ra Δ and Il10rb -/-RM.…”

Section: Transfer Of Wt Bm Overcomes Runx3 δ Bm-mediated Colitis Onsetsupporting

confidence: 53%

“…These results strongly indicate that loss of Runx3 in RM induces an anti-to proinflammatory switch in their biological properties. Comparison of RM DEGs in Runx3 Δ with those in Il10ra Δ and Il10rb -/-, that also induce colitis (Redhu et al, 2017;Zigmond et al, 2014), revealed gain of pro-inflammatory hallmarks in all three models of spontaneous colitis. Loss of Runx3 in RM did not affect expression of IL10ra and IL10rb in our data and neither was expression of Runx3 significantly affected by loss of Il10rb (Redhu et al, 2017).…”

Section: Discussionmentioning

confidence: 94%

“…Comparison of RM DEGs in Runx3 Δ with those in Il10ra Δ and Il10rb -/-, that also induce colitis (Redhu et al, 2017;Zigmond et al, 2014), revealed gain of pro-inflammatory hallmarks in all three models of spontaneous colitis. Loss of Runx3 in RM did not affect expression of IL10ra and IL10rb in our data and neither was expression of Runx3 significantly affected by loss of Il10rb (Redhu et al, 2017). Therefore, the similar spontaneous colitis phenotype in these three strains cannot be explained by cross-regulation between Runx3 and signals emanating from the Il10 receptors.…”

Section: Discussionmentioning

confidence: 94%

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Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes

Hantisteanu

Dicken

Negreanu

et al. 2019

Preprint

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RUNX3 is one of three mammalian Runt-domain transcription factors (TFs) that regulate gene expression in several types of immune cells. Runx3-deficiency in mice is associated with a multitude of defects in the adaptive and innate immunity systems, including the development of early onset colitis. Our study reveals that conditional deletion of Runx3 specifically in mononuclear phagocytes (MNP) (MNP Runx3-/-) but not in T cells, recapitulates the early onset spontaneous colitis seen in Runx3 -/mice.We show that Runx3 is expressed in colonic MNP, including resident macrophages (RM) and the dendritic cell cDC2 subsets and its loss results in impaired differentiation/maturation of both cell types. At the transcriptome level, loss of Runx3 in RM and cDC2 was associated with upregulation of pro-inflammatory genes similar to those in the early onset IBD murine model of RM Il10r-/-. The impaired RM maturation in the absence of Runx3 was associated with a marked decrease in expression of antiinflammatory and TGFb-regulated genes. Similarly, the decreased expression of b-

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Section: Transfer Of Wt Bm Overcomes Runx3 δ Bm-mediated Colitis Onsetsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes

Hantisteanu

Dicken

Negreanu

et al. 2019

Preprint

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“…Dissociated tissue was then passed through a 70 -µm strainer and washed twice in PBS (Lonza Biologics) to neutralize the collagenase activity, and stored on ice until analyzed by flow cytometry. The colon tissue was harvested, and lamina propria (LP) immune cells were prepared as described previously, 63 with minor modifications. Briefly, colons were stripped of epithelial cells by performing agitation in 10 mM EDTA (Thermo Fisher Scientific) for 30 min at 37°C before digestion in collagenase buffer (Sigma-Aldrich; collagenase type VIII; 200 U/ml, 20% FBS, 1.5 mM CaCl 2 in HBSS) for 30-45 min at 37°C with shaking at 220 rpm.…”

Section: Micementioning

confidence: 99%

Generation of protective pneumococcal-specific nasal resident memory CD4+ T cells via parenteral immunization

et al. 2020

Self Cite

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The generation of tissue-resident memory T cells (T RM ) is an essential aspect of immunity at mucosal surfaces, and it has been suggested that preferential generation of T RM is one of the principal advantages of mucosally administered vaccines. We have previously shown that antigen-specific, IL-17-producing CD4 + T cells can provide capsular antibody-independent protection against nasal carriage of Streptococcus pneumoniae; but whether pneumococcus-responsive T RM are localized within the nasal mucosa and are sufficient for protection from carriage has not been determined. Here, we show that intranasal administration of live or killed pneumococci to mice generates pneumococcus-responsive IL-17A-producing CD4 + mucosal T RM. Furthermore, we show that these cells are sufficient to mediate long-lived, neutrophil-dependent protection against subsequent pneumococcal nasal challenge. Unexpectedly, and in contrast with the prevailing paradigm, we found that parenteral administration of killed pneumococci also generates protective IL-17A + CD4 + T RM in the nasal mucosa. These results demonstrate a critical and sufficient role of T RM in prevention of pneumococcal colonization, and further that these cells can be generated by parenteral immunization. Our findings therefore have important implications regarding the generation of immune protection at mucosal surfaces by vaccination.Mucosal Immunology (2020) 13:172-182; https://doi.

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“…IL-10 plays a crucial role in the maintenance and regulation of mucosal immune tolerance and in the anti-inflammatory function of macrophages in the intestine [ 36 ]. In mice lacking the IL-10R, intestinal inflammation and macrophage dysfunction begin during the third week of life [ 37 ]. The role of macrophages in this context is highlighted when these cells are depleted leading to the protection from the development of colitis even in IL-10R-deficient mice [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Salivary Gland Extract of Kissing Bug, Triatoma lecticularia, Reduces the Severity of Intestinal Inflammation through the Modulation of the Local IL-6/IL-10 Axis

Sales‐Campos

Catarino

Roza

et al. 2018

Mediators of Inflammation

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Triatomines are known for their role as vectors of the causative agent of Chagas disease. The occurrence of an arsenal of molecules in their saliva is able to suppress vertebrate immune responses. Thus, it is reasonable to assume that the presence of molecules with therapeutic potential in their saliva is able to constrain inflammation in immune-mediated diseases. Thus, mice were exposed to dextran sulfate sodium (DSS) in drinking water uninterruptedly during 6 consecutive days and treated with T. lecticularia salivary gland extract (SGE) (3, 10, or 30 μg) or vehicle (saline) (n = 6/group). At the highest dose (30 μg), an improvement in clinical outcome and macroscopic aspects of the intestine were observed. This observation was followed by amelioration in histopathological aspects in the colon especially when the doses of 10 and 30 μg were used. Regardless of the concentration used, treatment with T. lecticularia SGE significantly reduced the levels of the inflammatory cytokine IL-6 in the intestine. The production of the anti-inflammatory cytokine IL-10 was positively impacted by the concentrations of 3 and 30 μg. Our results suggest that the presence of molecules in the T. lecticularia SGE is able to attenuate clinical outcome and colon shortening and improve intestinal architecture besides reducing the production of IL-6 and inducing a local production of IL-10 in the intestine.

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Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

Cited by 29 publications

References 55 publications

Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes

Runx3 prevents spontaneous colitis by directing differentiation of anti-inflammatory mononuclear phagocytes

Generation of protective pneumococcal-specific nasal resident memory CD4+ T cells via parenteral immunization

Salivary Gland Extract of Kissing Bug, Triatoma lecticularia, Reduces the Severity of Intestinal Inflammation through the Modulation of the Local IL-6/IL-10 Axis

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