p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis

Mihaescu, Andrada; Santén, Stefan; Jeppsson, Bengt; Thorlacius, Henrik

doi:10.1002/bjs.6811

Cited by 27 publications

(21 citation statements)

References 42 publications

(56 reference statements)

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“…After TBI, Akt/mTOR and their active forms, Notch, beta-catenin, NFkB, and their downstream targets were markedly downregulated in IECs from Villin Cre ;Dclk1 f/f mice compared with IECs from Dclk1 f/f mice. Intestinal epithelial integrity is a necessary component in maintaining intestinal epithelial homeostasis and during regeneration after injury5253. Loss of intestinal epithelial integrity and increased permeability due to impaired expression of tight and adherens junction proteins in Villin Cre ;Dclk1 f/f mice, even 3.5 days post-TBI, may account for defective restitution responses.…”

Section: Discussionmentioning

confidence: 99%

Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury

Chandrakesan

May

Weygant

et al. 2016

Sci Rep

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Crypt epithelial survival and regeneration after injury require highly coordinated complex interplay between resident stem cells and diverse cell types. The function of Dclk1 expressing tuft cells regulating intestinal epithelial DNA damage response for cell survival/self-renewal after radiation-induced injury is unclear. Intestinal epithelial cells (IECs) were isolated and purified and utilized for experimental analysis. We found that small intestinal crypts of VillinCre;Dclk1f/f mice were hypoplastic and more apoptotic 24 h post-total body irradiation, a time when stem cell survival is p53-independent. Injury-induced ATM mediated DNA damage response, pro-survival genes, stem cell markers, and self-renewal ability for survival and restitution were reduced in the isolated intestinal epithelial cells. An even greater reduction in these signaling pathways was observed 3.5 days post-TBI, when peak crypt regeneration occurs. We found that interaction with Dclk1 is critical for ATM and COX2 activation in response to injury. We determined that Dclk1 expressing tuft cells regulate the whole intestinal epithelial cells following injury through paracrine mechanism. These findings suggest that intestinal tuft cells play an important role in regulating the ATM mediated DNA damage response, for epithelial cell survival/self-renewal via a Dclk1 dependent mechanism, and these processes are indispensable for restitution and function after severe radiation-induced injury.

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Section: Discussionmentioning

confidence: 99%

Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury

Chandrakesan

May

Weygant

et al. 2016

Sci Rep

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“…While little is known about the role of NF-B in determining the contribution of IECs to C. rodentium colitis, we and others recently showed that IEC-specific p38 MAPK signaling plays a major role in the immune and inflammatory response to C. rodentium infection (25,42), in keeping with our findings that the ⌬nleC strain triggered greater chemokine responses in vivo. It has been recently reported that p38 MAPK modulates NF-B signaling during C. rodentium infection (4), and both of these signaling pathways are important in MIP-2, MIP-3␣, and KC production by epithelial cells (33,39,51). By suppressing both NF-B and p38 MAPK activation, C. rodentium likely suppresses the local inflammatory response, creating a protected niche in the intestine.…”

Section: Discussionmentioning

confidence: 99%

Attaching and Effacing Bacterial Effector NleC Suppresses Epithelial Inflammatory Responses by Inhibiting NF-κB and p38 Mitogen-Activated Protein Kinase Activation

et al. 2011

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Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli are noninvasive attaching and effacing (A/E) bacterial pathogens that cause intestinal inflammation and severe diarrheal disease. These pathogens utilize a type III secretion system to deliver effector proteins into host epithelial cells, modulating diverse cellular functions, including the release of the chemokine interleukin-8 (IL-8). While studies have implicated the effectors NleE (non-locus of enterocyte effacement [LEE]-encoded effector E) and NleH1 in suppressing IL-8 release, by preventing NF-B nuclear translocation, the impact of these effectors only partially replicates the immunosuppressive actions of wild-type EPEC, suggesting another effector or effectors are involved. Testing an array of EPEC mutants, we identified the non-LEE-encoded effector C (NleC) as also suppressing IL-8 release. Infection by ⌬nleC EPEC led to exaggerated IL-8 release from infected Caco-2 and HT-29 epithelial cells. NleC localized to EPEC-induced pedestals, with signaling studies revealing NleC inhibits both NF-B and p38 mitogen-activated protein kinase (MAPK) activation. Using Citrobacter rodentium, a mouse-adapted A/E bacterium, we found that ⌬nleC and wild-type C. rodentium-infected mice carried similar pathogen burdens, yet ⌬nleC strain infection led to worsened colitis. Similarly, infection with ⌬nleC C. rodentium in a cecal loop model induced significantly greater chemokine responses than infection with wild-type bacteria. These studies thus advance our understanding of how A/E pathogens subvert host inflammatory responses.

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“…Thus, the chemokine-mediated mechanisms behind accumulation of neutrophils in the lung are relatively well known, whereas the signaling pathways regulating M1 protein-induced neutrophil recruitment and tissue damage in the lung remain elusive. A broad range of stress stimuli, such as ischemia/reperfusion [14,15], radiation [16], heat shock [17], microbial toxins [18], and infections [19,20], is integrated and transmitted intracellularly via MAPKs, including p38 MAPK, ERK1/2, and JNKs [21]. Signal transduction through MAPKs controls production of proinflammatory cytokines and chemokines [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

p38 Mitogen-activated protein kinase signaling regulates streptococcal M1 protein-induced neutrophil activation and lung injury

Zhang

Rahman

Zhang

et al. 2011

Journal of Leukocyte Biology

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M1 serotype of Streptococcus pyogenes can cause STSS and acute lung damage. Herein, the purpose was to define the role of p38 MAPK signaling in M1 protein-induced pulmonary injury. Male C57BL/6 mice were treated with specific p38 MAPK inhibitors (SB 239063 and SKF 86002) prior to M1 protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 protein administration. Flow cytometry was used to determine Mac-1 expression. Phosphorylation and activity of p38 MAPK were determined by immunoprecipitation and Western blot. IVM was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. M1 protein challenge increased phosphorylation and activity of p38 MAPK in the lung, which was inhibited by SB 239063 and SKF 86002. Inhibition of p38 MAPK activity decreased M1 protein-induced infiltration of neutrophils, edema, and CXC chemokine formation in the lung, as well as Mac-1 up-regulation on neutrophils. IVM showed that p38 MAPK inhibition reduced leukocyte rolling and adhesion in the pulmonary microvasculature of M1 protein-treated mice. Our results indicate that p38 MAPK signaling regulates neutrophil infiltration in acute lung injury induced by streptococcal M1 protein. Moreover, p38 MAPK activity controls CXC chemokine formation in the lung, as well as neutrophil expression of Mac-1 and recruitment in the pulmonary microvasculature. In conclusion, these findings suggest that targeting the p38 MAPK signaling pathway may open new opportunities to protect against lung injury in streptococcal infections.

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p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis

Abstract: : p38 MAPK is an important signalling pathway in radiation-induced colitis.

Cited by 27 publications

References 42 publications

Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury

Intestinal tuft cells regulate the ATM mediated DNA Damage response via Dclk1 dependent mechanism for crypt restitution following radiation injury

Attaching and Effacing Bacterial Effector NleC Suppresses Epithelial Inflammatory Responses by Inhibiting NF-κB and p38 Mitogen-Activated Protein Kinase Activation

p38 Mitogen-activated protein kinase signaling regulates streptococcal M1 protein-induced neutrophil activation and lung injury

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