TLR Signaling Paralyzes Monocyte Chemotaxis through Synergized Effects of p38 MAPK and Global Rap-1 ActivationReport as inadecuate

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Toll-like receptors TLRs that recognize pathogen associated molecular patterns and chemoattractant receptors CKRs that orchestrate leukocyte migration to infected tissue are two arms of host innate immunity. Although TLR signaling induces synthesis and secretion of proinflammatory cytokines and chemokines, which recruit leukocytes, many studies have reported the paradoxical observation that TLR stimulation inhibits leukocyte chemotaxis in vitro and impairs their recruitment to tissues during sepsis. There is consensus that physical loss of chemokine receptor CKR at the RNA or protein level or receptor usage switching are the mechanisms underlying this effect. We show here that a brief <15 min stimulation with LPS lipopolysaccharide at ∼0.2 ng-ml inhibited chemotactic response from CCR2, CXCR4 and FPR receptors in monocytes without downmodulation of receptors. A 3 min LPS pre-treatment abolished the polarized accumulation of F-actin, integrins and PIP3 phosphatidylinositol-3,4,5-trisphosphate in response to chemokines in monocytes, but not in polymorphonuclear neutrophils PMNs. If chemoattractants were added before or simultaneously with LPS, chemotactic polarization was preserved. LPS did not alter the initial G-protein signaling, or endocytosis kinetics of agonist-occupied chemoattractant receptors CKRs. The chemotaxis arrest did not result from downmodulation of receptors or from inordinate increase in adhesion. LPS induced rapid p38 MAPK activation, global redistribution of activated Rap1 Ras-proximate-1 or Ras-related protein 1 GTPase and Rap1GEF guanylate exchange factor Epac1 exchange proteins activated by cyclic AMP and disruption of intracellular gradient. Co-inhibition of p38 MAPK and Rap1 GTPase reversed the LPS induced breakdown of chemotaxis suggesting that LPS effect requires the combined function of p38 MAPK and Rap1 GTPase.

Author: Ling Yi, Prabha Chandrasekaran, Sundararajan Venkatesan



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