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.
Macrophages express CD14 which partners with Toll-like receptor 2/1 to recognize bacterial lipoproteins such as those of Borrelia burgdorferi, the causative agent of Lyme disease. In vitro evidence demonstrates that blocking CD14 recognition of bacterial components ablates innate host cell inflammatory responses. Similarly, blocking downstream p38 kinase activity dampens the cellular response to these same microbial stimuli. This body of work underpins two well-established paradigms which cite the primacy of CD14 in facilitating TLR recognition of microbes to initiate proinflammatory signaling events and the importance of p38 in augmenting such responses. However, contrary to these paradigms, our prior study using a mouse model of Lyme disease demonstrated an association between CD14 deficiency, increased bacterial burden, and more severe and persistent disease. Herein, we provide a mechanistic explanation for this unanticipated host immune response implicating impaired negative regulation of inflammatory signaling pathways as an underlying cause. Consequent to impaired negative regulation the host becomes “intolerant” of continued exposure to bacteria and thus mounts a perpetual inflammatory response to their presence. An intriguing question raised by these findings is whether individual differences in the severity and clinical course of infection might reflect the susceptibility of the patient's innate immune system to tolerization.