CXCL4 signaling and gene induction in human monocytes involve a TLR4 response divergent from LPS
The chemokine CXCL4 activates myeloid cells and contributes to the pathogenesis of inflammatory and fibrotic diseases. One mechanism of CXCL4 action is binding of nucleic acids to promote their internalization and activation of endosomal TLRs. However, the signaling pathways and receptors that mediate myeloid cell responses to CXCL4 alone are not well characterized. Here, we report that in primary human monocytes, CXCL4 activated NF-{kappa}B and a TBK1-JNK signaling axis that drive the expression of inflammatory, fibrotic and neutrophil chemokine genes, and also RIPK3-dependent necroptosis. Surprisingly, six distinct lines of evidence targeting TLR4 expression and function suggested a role for TLR4 in CXCL4 responses. However, we were not able to completely dissect the contributions of CXCL4 alone to the observed results versus a contribution from endotoxin contamination. Our findings suggest that the interactions between CXCL4 and TLR4 merit further study.