Involvement of β1 integrin in microglial chemotaxis and proliferation on fibronectin: Different regulations by ADP through PKA

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Abstract
Microglia are immune cells in the brain; their activation, migration, and proliferation have pivotal roles in brain injuries and diseases. Microglia are known to attach firmly to fibronectin, the upregulation of which is associated with several pathological conditions in the CNS, through β1 integrin and become activated. Extracellular nucleotides can serve as potent signaling molecules. Recently, ATP and ADP were revealed to possess chemoattractive properties to microglia via Gi‐coupled P2Y receptors. In the present study, we report that the ADP‐induced chemotaxis of microglia is mediated by P2Y12/13 receptors and is β1 integrin‐dependent in the presence of fibronectin. Signals from P2Y12/13 receptors also cause β1 integrin translocation to the membrane ruffle regions, but this redistribution was lost when the intracellular cyclic AMP (cAMP) was increased by forskolin or dibutyryl cAMP. This inhibitory effect of cAMP‐elevating agents did not appear when microglia were co‐incubated with a protein kinase A (PKA) inhibitor, KT‐5720, suggesting that PKA is a negative regulator of the β1 integrin translocation. We also show that the engagement of β1 integrin enhanced microglial proliferation. Signals from P2Y12/13 receptors attenuated the proliferation, whereas ADP itself had no effect on microglial growth. Furthermore, β1 integrin‐induced proliferation is positively regulated by the cAMP‐dependent PKA. Together, these results indicate the involvement of β1 integrin in microglial proliferation and chemotaxis, both of which have clinical importance. The data also suggest that PKA is inversely involved in these two cellular functions.