CD14 Signaling Restrains Chronic Inflammation

Current thinking emphasizes the primacy of CD14 in facilitating
recognition of microbes by certain TLRs to initiate pro-inflammatory
signaling events and the importance of p38-MAPK in augmenting such
responses. Herein, this paradigm is challenged by demonstrating that
recognition of live Borrelia burgdorferi not only triggers an
inflammatory response in the absence of CD14, but one that is, in part,
a consequence of altered PI3K/AKT/p38-MAPK signaling and impaired
negative regulation of TLR2. CD14 deficiency results in increased
localization of PI3K to lipid rafts, hyperphosphorylation of AKT, and
reduced activation of p38. Such aberrant signaling leads to decreased
negative regulation by SOCS1, SOCS3, and CIS, thereby compromising the
induction of tolerance in macrophages and engendering more severe and
persistent inflammatory responses to B. burgdorferi. Importantly, these
altered signaling events and the higher cytokine production observed can
be mimicked through shRNA and pharmacological inhibition of p38 activity
in CD14-expressing macrophages. Perturbation of this
CD14/p38-MAPK-dependent immune regulation may underlie development of
infectious chronic inflammatory syndromes.