MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice

Gabriella Aviello, Sinéad C Corr, Daniel G W Johnston, Luke A J O'Neill, Padraic G Fallon

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.

Original languageEnglish
Pages (from-to)G769-778
Number of pages10
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
Volume306
Issue number9
DOIs
Publication statusPublished - 1 May 2014

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Colitis
Colorectal Neoplasms
Dextran Sulfate
Homeostasis
Azoxymethane
Inflammation
Maintenance
Neoplasms
Colon
Myeloid Differentiation Factor 88
Whole-Body Irradiation
Toll-Like Receptors
Bone Marrow Transplantation
Bone Marrow
Incidence
Wounds and Injuries

Keywords

  • Animals
  • Azoxymethane
  • Bone Marrow Transplantation
  • Caco-2 Cells
  • Colitis
  • Colon
  • Colorectal Neoplasms
  • Dextran Sulfate
  • Disease Models, Animal
  • Female
  • Homeostasis
  • Humans
  • Male
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Interleukin-1
  • Severity of Illness Index
  • Time Factors
  • Transplantation Chimera
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice. / Aviello, Gabriella; Corr, Sinéad C; Johnston, Daniel G W; O'Neill, Luke A J; Fallon, Padraic G.

In: American journal of physiology. Gastrointestinal and liver physiology , Vol. 306, No. 9, 01.05.2014, p. G769-778.

Research output: Contribution to journalArticle

Aviello, Gabriella ; Corr, Sinéad C ; Johnston, Daniel G W ; O'Neill, Luke A J ; Fallon, Padraic G. / MyD88 adaptor-like (Mal) regulates intestinal homeostasis and colitis-associated colorectal cancer in mice. In: American journal of physiology. Gastrointestinal and liver physiology . 2014 ; Vol. 306, No. 9. pp. G769-778.
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AU - Aviello, Gabriella

AU - Corr, Sinéad C

AU - Johnston, Daniel G W

AU - O'Neill, Luke A J

AU - Fallon, Padraic G

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AB - Toll-like receptors (TLRs) play a central role in the recognition and response to microbial pathogens and in the maintenance and function of the epithelial barrier integrity in the gut. The protein MyD88 adaptor-like (Mal/TIRAP) serves as a bridge between TLR2/TLR4- and MyD88-mediated signaling to orchestrate downstream inflammatory responses. Whereas MyD88 has an essential function in the maintenance of intestinal homeostasis, a role for Mal in this context is less well described. Colitis was induced in wild-type (WT) and Mal-deficient (Mal(-/-)) mice by administration of dextran sodium sulfate (DSS). Colitis-associated cancer was induced by DSS and azoxymethane (AOM) treatment. Chimeric mice were generated by total body gamma irradiation followed by transplantation of bone marrow cells. In the DSS model of colon epithelial injury, Mal(-/-) mice developed increased inflammation and severity of colitis relative to WT mice. Mal(-/-) mice demonstrated the presence of inflammatory cell infiltrates, increased crypt proliferation, and presence of neoformations. Furthermore, in the AOM/DSS model, Mal(-/-) mice had greater incidence of tumors. Mal(-/-) and WT bone marrow chimeras demonstrated that nonhematopoietic cell expression of Mal had an important protective role in the control of intestinal inflammation and inflammation-associated cancer. Mal is essential for the maintenance of intestinal homeostasis and expression of Mal in nonhematopoietic cells prevents chronic intestinal inflammation that may predispose to colon neoplasia.

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KW - Homeostasis

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KW - Male

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KW - Receptors, Interleukin-1

KW - Severity of Illness Index

KW - Time Factors

KW - Transplantation Chimera

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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VL - 306

SP - G769-778

JO - American journal of physiology. Gastrointestinal and liver physiology

JF - American journal of physiology. Gastrointestinal and liver physiology

SN - 1522-1547

IS - 9

ER -