β2 integrins inhibit TLR responses by regulating NF-κB pathway and p38 MAPK activation

Outside-in signals from 2 integrins require immunoreceptor tyrosine-based activation motif adapters in myeloid cells that are known to dampen TLR responses. However, the relationship between 2 integrins and TLR regulation is unclear. Here we show that deficiency in 2 integrins (Itgb2/) causes hyperresponsiveness to TLR stimulation, demonstrating that 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 IB degradation, leading to changes in NF-B recruitment to target promoters and elevated cytokine, chemokine, and anti-apoptotic gene transcription. Thus, 2 integrins limit TLR signaling by inhibiting NF-B pathway activation and promoting p38 MAPK activation, thereby fine-tuning TLR-induced inflammatory responses.