Interleukin-33 safeguards neutrophils in sepsis (1)
IL-33 signaling prevented Toll-like receptor (TLR)-mediated downregulation of CXCR2 expression in mouse and human neutrophils, which enhanced neutrophil recruitment to the site of infection and bacterial clearance. TLRs are essential in the sensing of conserved microbial molecular motifs. Upon ligand binding, these sensors activate a complex cellular response that results in the production of numerous cytokines and chemokines implicated in the initiation, amplification and regulation of the host antimicrobial defense response.
IL-33 has been implicated in the pathogenesis of asthma, atopic allergy, anaphylaxis and cardiovascular diseases. IL-33 signals through a heterodimeric receptor complex composed
of ST2 and IL-1 receptor accessory protein, promoting the production of proinflammatory cytokines and a T helper type 2 immune response.
Administering IL-33 to a stringent sepsis model mice markedly enhanced the influx of neutrophils into the infectious focus, reducing bacterial counts and increasing survival. In addition, treatment of septic mice with IL-33 overcame CXCR2 downregulation and chemotaxis inhibition of neutrophils exposed to microbial products. Activation of TLR2 by bacterial lipopeptides can also induce apoptosis of neutrophils, enhancing bacterial proliferation and mortality caused by bacterial sepsis.
IL-33 receptor complex and TLRs initiate signaling through the recruitment of myeloid differentiation factor-88 (MyD88)—but in neutrophils IL-33 downregulates GRK2 expression, whereas TLRs mediate GRK2 upregulation. IL-33 upregulates the expression of TLR4 and MyD88 and enhances LPS-induced cytokine produc- tion, whereas ST2 acts as a negative regulator of TLR4 and IL-1 receptor signaling.
