Inducible Colonic M Cells Are Dependent on TNFR2 but Not Ltβr, Identifying Distinct Signalling Requirements for Constitutive Versus Inducible M Cells.
Background and Aims
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.
['Parnell|Erinn A|EA|', 'Walch|Erin M|EM|', 'Lo|David D|DD|']
D000818:Animals D003092:Colitis D003106:Colon D016264:Dextran Sulfate D018928:Immunity, Mucosal D007249:Inflammation D007413:Intestinal Mucosa D053259:Lymphotoxin beta Receptor D051379:Mice D010581:Peyer's Patches D053245:RANK Ligand D047888:Receptors, Tumor Necrosis Factor, Type I D047889:Receptors, Tumor Necrosis Factor, Type II D015398:Signal Transduction
M cell DSS Colitis TNF alpha lymphotoxin beta