title: β(2) integrins inhibit TLR responses by regulating NF-κB pathway and p38 MAPK activation.
abstract: Outside-in signals from β(2) integrins require immunoreceptor tyrosine-based activation motif adapters in myeloid cells that are known to dampen TLR responses. However, the relationship between β(2) integrins and TLR regulation is unclear. Here we show that deficiency in β(2) integrins (Itgb2(-/-) ) causes hyperresponsiveness to TLR stimulation, demonstrating that β(2) integrins inhibit signals downstream of TLR ligation. Itgb2(-/-) macrophages and dendritic cells produced more IL-12 and IL-6 than WT cells when stimulated with TLR agonists and Itgb2(-/-) mice produced more inflammatory cytokines than WT mice when injected with LPS. TLR hypersensitivity was not the result of insufficient ABIN-3, A20, Hes-1, or IRAK-M expression, nor to changes in IL-10 production or sensitivity, though Itgb2(-/-) macrophages had reduced p38 MAPK phosphorylation after LPS treatment. Furthermore, a Cbl-b-MyD88 regulatory axis is not required for TLR inhibition in macrophages. Instead, Itgb2(-/-) macrophages presented with enhanced IκBα degradation, leading to changes in NF-κB recruitment to target promoters and elevated cytokine, chemokine, and anti-apoptotic gene transcription. Thus, β(2) integrins limit TLR signaling by inhibiting NF-κB pathway activation and promoting p38 MAPK activation, thereby fine-tuning TLR-induced inflammatory responses.
authors: Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA.
authors: Nathan K
authors: NK
authors: Yee
authors: Jessica A
authors: JA
authors: Hamerman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D040881:CD11a Antigen / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D040881:CD11a Antigen; D039481:CD11b Antigen; D018821:CD18 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C503281:Tnip2 protein, mouse; D051193:Toll-Like Receptors; D044767:Ubiquitin-Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse