Identifying platelet-derived factors as amplifiers of B. burgdorferi-induced cytokine production

In this study, we observed that B. burgdorferidecreased cytokine production in response to the TLR4-ligand lipopolysaccharide (LPS) and glycolysis was lowered by cells exposed to B. burgdorfericompared to medium control. We found a gene, microfibril-associated protein 3-like (MFAP3L), that influences lactate production following B. burgdorferistimulation and MFAP3L could mediate this effect by activating ERK2 and platelet activation and degranulation. A specific platelet-derived factor, CXCL7, was associated with B. burgdorferi-induced cytokine production and was found to be elevated in plasma and serum of erythema migrans patients, the most common disease manifestation of Lyme borreliosis. Previous studies have shown that monocytes can be 'trained' or tolerized by certain stimuli to respond stronger or weaker to a secondary stimulation. Rewiring of glucose metabolism was found to be important in inducing this phenotype. As we previously found that Borrelia burgdorferi (B. burgdorferi), the causative agent of Lyme borreliosis (LB), alters glucose metabolism in monocytes, we hypothesized that this may also induce long-term changes in innate immune responses. We found that exposure to B. burgdorferi decreased cytokine production in response to the TLR4-ligand lipopolysaccharide (LPS). In addition, B. burgdorferi exposure decreased baseline levels of glycolysis, as assessed by lactate production. Using GWAS analysis, we identified a gene, microfibril-associated protein 3-like (MFAP3L) as a factor influencing lactate production after B. burgdorferi exposure. Validation experiments proved that MFAP3L affects lactate- and cytokine production following B. burgdorferi stimulation. This is mediated by functions of MFAP3L, which includes activating ERK2 and through activation of platelet degranulation. Moreover, we showed that platelets and platelet-derived factors play important roles in B. burgdorferi-induced cytokine production. Certain platelet-derived factors, such chemokine C-X-C motif ligand 7 (CXCL7) and (C-C motif) ligand 5 (CCL5), were elevated in the circulation of LB patients in comparison to healthy individuals.

Automated summary

This study reveals that B. burgdorferi infection decreases cytokine production in cells and lowers glycolysis. MFAP3L gene is found to influence lactate production and mediate this effect through ERK2 activation and platelet degranulation. Platelet-derived factors, such as CXCL7, play important roles in B. burgdorferi-induced cytokine production.