MicroRNA‐146a‐mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury

Chassin, Cécilia; Hempel, Cordelia; Stockinger, Silvia; Dupont, Aline; Kübler, J.; Wedemeyer, Jochen; Vandewalle, Alain; Hornef, Mathias W.

doi:10.1002/emmm.201201298

Cited by 77 publications

(69 citation statements)

References 55 publications

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“…18,19 We found that intraperitoneal injection or oral administration of DIM as previously reported 20,21 improved survival and decreased GVHD severity in allo-HCT mice (supplemental Figure 1B-D) and augmented miR-146a expression (supplemental Figure 1E-F). Although these results demonstrate the potential of phytochemical therapy to promote tolerogenic miR-146a effects, the precise mechanisms of immune modulation involved are less clear.…”

Section: Exogenous Increase Of Mir-146a Expression Protects Against Gvhdsupporting

confidence: 76%

MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD

Stickel

Prinz

Pfeifer

et al. 2014

Blood

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Section: Exogenous Increase Of Mir-146a Expression Protects Against Gvhdsupporting

confidence: 76%

MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD

Stickel

Prinz

Pfeifer

et al. 2014

Blood

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“…Furthermore, mice lacking IRAK1 fail to mount an inflammatory response and produce significantly lower levels of proinflammatory cytokines, suggesting their critical requirement for activation of the NF-B signaling pathway and the subsequent inflammatory response (23). Finally, recent studies have confirmed the central role of IRAK1 in driving intestinal inflammation (50,51). Consistent with miR-150 downregulation, IRAK1 protein expression significantly increased in colonic LPLs of chronically SIV-infected macaques.…”

Section: Discussionmentioning

confidence: 88%

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

Kumar

Torben

Kenway

et al. 2016

J Virol

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Chronic immune activation/inflammation driven by factors like microbial translocation is a key determinant of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) disease progression. Although extensive research on inflammation has focused on studying protein regulators, increasing evidence suggests a critical role for microRNAs (miRNAs) in regulating several aspects of the immune/inflammatory response and immune cell proliferation, differentiation, and activation. To understand their immunoregulatory role, we profiled miRNA expression sequentially in intestinal lamina propria leukocytes (LPLs) of eight macaques before and at 21, 90, and 180 days postinfection (dpi). At 21 dpi, ϳ20 and 9 miRNAs were up-and downregulated, respectively. However, at 90 dpi (n ‫؍‬ 60) and 180 dpi (n ‫؍‬ 44), >75% of miRNAs showed decreased expression. Notably, the T-cell activation-associated miR-15b, miR-142-3p, miR-142-5p, and miR-150 expression was significantly downregulated at 90 and 180 dpi. Out of ϳ10 downregulated miRNAs predicted to regulate CD69, we confirmed miR-92a to directly target CD69. Interestingly, the SIV-induced miR-190b expression was elevated at all time points. Additionally, elevated lipopolysaccharide (LPS)-responsive miR-146b-5p expression at 180 dpi was confirmed in primary intestinal macrophages following LPS treatment in vitro. A major hallmark of untreated human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) infection is chronic generalized immune activation and inflammation that is linked to viral replication, loss of CD4 ϩ T cells, immunological dysfunction, and disease progression (1-3). Further, chronic immune activation has been reported to persist even in HIV-infected individuals successfully treated with combination antiretroviral therapy (cART), suggesting that proinflammatory signaling does not completely subside in treated individuals (4). While the exact mechanisms driving chronic immune activation in HIV/SIV infection remain to be determined, several independent studies have implicated HIV persistence, coinfections with hepatitis C virus/ hepatitis B virus/cytomegalovirus (HCV/HBV/CMV), compensatory homeostatic mechanisms, and chronic stimulation by translocated intestinal microbial products to drive this phenomenon. Among these, microbial translocation from a structurally and functionally damaged gastrointestinal (GI) tract has received considerable attention and is considered to significantly contribute to

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“…These experiments demonstrated that IRAK1 expression in T cells is required for induction of severe colitis and that IRAK1 expression outside of the T cell compartment, for example in APCs, innate lymphoid cells, intestinal epithelial cells, and stroma cells (11,33), additionally contributes to development of T cell-dependent colitis. This was also suggested by reduced susceptibility of Irak1-deficient mice to acute DSS-induced colitis (Ref.…”

Section: /2mentioning

confidence: 93%

IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity

Heiseke¹,

Jeuk²,

Markota³

et al. 2015

The Journal of Immunology

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IL-1R–associated kinase (IRAK) 1 is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. In this study, we show that IRAK1 promotes Th17 development by mediating IL-1β–induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts regulatory T cell generation. Cotransfer experiments revealed that Irak1-deficient CD4+ T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes, and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mesenteric lymph nodes. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of α4β7 integrin after transfer into Rag1−/− mice, and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation, and accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.

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MicroRNA‐146a‐mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury

Cited by 77 publications

References 55 publications

MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD

MiR-146a regulates the TRAF6/TNF-axis in donor T cells during GVHD

Longitudinal Examination of the Intestinal Lamina Propria Cellular Compartment of Simian Immunodeficiency Virus-Infected Rhesus Macaques Provides Broader and Deeper Insights into the Link between Aberrant MicroRNA Expression and Persistent Immune Activation

IRAK1 Drives Intestinal Inflammation by Promoting the Generation of Effector Th Cells with Optimal Gut-Homing Capacity

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