β2 Integrins Are Involved in Cytokine Responses to Whole Gram-Positive Bacteria

Abstract

Proinflammatory cytokines have an important pathophysiologic role in septic shock. CD14 is involved in cytokine responses to a number of purified bacterial products, including LPS. However, little is known of monocyte receptors involved in cytokine responses to whole bacteria. To identify these receptors, human monocytes were pretreated with different mAbs and TNF-α was measured in culture supernatants after stimulation with whole heat-killed bacteria. Human serum and anti-CD14 Abs significantly increased and decreased, respectively, TNF-α responses to the Gram-negative Escherichia coli. However, neither treatment influenced responses to any of the Gram-positive bacteria tested, including group A and B streptococci, Listeria monocytogenes, and Staphylococcus aureus. Complement receptor type III (CR3 or CD18/CD11b) Abs prevented TNF-α release induced by heat-killed group A or B streptococci. In contrast, the same Abs had no effects when monocytes were stimulated with L. monocytogenes or S. aureus. Using either of the latter bacteria, significant inhibition of TNF-α release was produced by Abs to CD11c, one of the subunits of CR4. To confirm these blocking Ab data, IL-6 release was measured in CR3-, CR4-, or CD14-transfected Chinese hamster ovary cells after bacterial stimulation. Accordingly, streptococci triggered moderate IL-6 production (p < 0.05) in CR3 but not CD14 or CR4 transfectants. In contrast, L. monocytogenes and S. aureus induced IL-6 release in CR4 but not CR3 or CD14 transfectants. Collectively our data indicate that β2 integrins, such as CR3 and CR4, may be involved in cytokine responses to Gram-positive bacteria. Moreover, CD14 may play a more important role in responses to whole Gram-negative bacteria relative to Gram-positive ones.

iC3b‐opsonized apoptotic cells mediate a distinct anti‐inflammatory response and transcriptional NF‐κB‐dependent blockade

“…An alternative scenario is that inhibition is triggered by the binding of iC3b-opsonized apoptotic cells to CD11b/CD18 and CD11c/CD18. CD11b/CD18 and CD11c/CD18 were reported as being both pro-and anti-inflammatory [42,43]. However, binding and phagocytosis via the CD11b/CD18 macrophage does not trigger leukotriene release [44] or a respiratory burst [45,46], suggesting noninflammatory functioning.…”

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

“…Our prior studies have indicated that S. epidermidis-triggered inflammatory responses are concentration dependent and, at high concentrations of bacteria and/or later time points, can proceed via TLR2-independent pathways both in vitro (cultured macrophages) and in vivo (cytokinemia) [18]. Accordingly, engagement of additional TLR2-independent pattern-recognition receptor pathways, such as NOD-like receptors, β-integrins, C-type lectins, inflammasomes, or other innate pathways [46][47][48][49], may contribute to S. epidermidis bacteremia-induced brain injury, especially at high concentrations of bacteria, and should be characterized in future studies. Consistent with these observations, Streptococcus pneumoniae induced neuronal injury within hours of bacteremia in adult mice, preceding detectable CNS penetration that was only partially mitigated in TLR2-deficient animals [9].…”

Cellular Activation, Phagocytosis, and Bactericidal Activity Against Group B Streptococcus Involve Parallel Myeloid Differentiation Factor 88-Dependent and Independent Signaling Pathways

“…These macrophages have an especially rich diversity of receptor proteins complementing the diversity of microbial molecules that they are likely to encounter, often in the context of soluble opsonins such as complement or LPS-binding protein. Two membrane proteins, the ␤ 2 -integrin CD11b/CD18 (complement receptor 3 (CR3)) and the glycoprotein CD14, have been suggested to be integral parts of receptor complexes essential for proinflammatory signaling and have been implicated in the activation of the innate immune response by GBS (5)(6)(7)(8)(9)(10)(11). However, neither CD14, which is attached to the cell membrane by a glycosyl phosphatidylinositol anchor, nor CD11b/ CD18, which has no known direct inflammatory signaling capabilities, can be expected to actually transfer the binding signal to a cytoplasmic signaling cascade (12,13).…”