title: Inducible Colonic M Cells Are Dependent on TNFR2 but Not Ltβr, Identifying Distinct Signalling Requirements for Constitutive Versus Inducible M Cells.
abstract: OBJECTIVE
  M cells associated with organised lymphoid tissues such as intestinal Peyer's patches provide surveillance of the intestinal lumen. Inflammation or infection in the colon can induce an M cell population associated with lymphoid infiltrates; paradoxically, induction is dependent on the inflammatory cytokine tumour necrosis factor [TNF]-α. Anti-TNFα blockade is an important therapeutic in inflammatory bowel disease, so understanding the effects of TNFα signalling is important in refining therapeutics.
  
  
  METHODS
  To dissect pro-inflammatory signals from M cell inductive signals, we used confocal microscopy image analysis to assess requirements for specific cytokine receptor signals using TNF receptor 1 [TNFR1] and 2 [TNFR2] knockouts [ko] back-crossed to the PGRP-S-dsRed transgene; separate groups were treated with soluble lymphotoxin β receptor [sLTβR] to block LTβR signalling. All groups were treated with dextran sodium sulphate [DSS] to induce colitis.
  
  
  RESULTS
  Deficiency of TNFR1 or TNFR2 did not prevent DSS-induced inflammation nor induction of stromal cell expression of receptor activator of nuclear factor kappa-B ligand [RANKL], but absence of TNFR2 prevented M cell induction. LTβR blockade had no effect on M cell induction, but it appeared to reduce RANKL induction below adjacent M cells.
  
  
  CONCLUSIONS
  TNFR2 is required for inflammation-inducible M cells, indicating that constitutive versus inflammation-inducible M cells depend on different triggers. The inducible M cell dependence on TNFR2 suggests that this specific subset is dependent on TNFα in addition to a presumed requirement for RANKL. Since inducible M cell function will influence immune responses, selective blockade of TNFα may affect colonic inflammation.
authors.affiliation: Division of Biomedical Sciences, University of California Riverside School of Medicine,Riverside, CA, USA.
authors.forename: Erinn A
authors.initials: EA
authors.lastname: Parnell
authors.affiliation: Division of Biomedical Sciences, University of California Riverside School of Medicine,Riverside, CA, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Walch
authors.affiliation: Division of Biomedical Sciences, University of California Riverside School of Medicine,Riverside, CA, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Lo
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology; D018928:Immunity, Mucosal; D007249:Inflammation / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D053259:Lymphotoxin beta Receptor / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D010581:Peyer's Patches / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053259:Lymphotoxin beta Receptor; D053245:RANK Ligand; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; C505689:Tnfsf11 protein, mouse; D016264:Dextran Sulfate
keywords: Colitis; DSS; M cell; TNF alpha; lymphotoxin beta