A multi-omic analysis reveals the regulatory role of CD180 during the response of macrophages to Borrelia burgdorferi

Abstract

Macrophages are cells of the innate immune system with the ability to phagocytose and induce a global pattern of responses that depend on several signaling pathways. We have determined the biosignature of murine bone marrow-derived macrophages and human blood monocytes using transcriptomic and proteomic approaches. We identified a common pattern of genes that are transcriptionally regulated and overall indicate that the response to B. burgdorferi involves the interaction of spirochetal antigens with several inflammatory pathways corresponding to primary (triggered by pattern-recognition receptors) and secondary (induced by proinflammatory cytokines) responses. We also show that the Toll-like receptor family member CD180 is downregulated by the stimulation of macrophages, but not monocytes, with the spirochete. Silencing Cd180 results in increased phagocytosis while tempering the production of the proinflammatory cytokine TNF. Cd180-silenced cells produce increased levels of Itgam and surface CD11b, suggesting that the regulation of CD180 by the spirochete initiates a cascade that increases CR3-mediated phagocytosis of the bacterium while repressing the consequent inflammatory response.

Regulation of macrophage activity by surface receptors contained within Borrelia burgdorferi-enriched phagosomal fractions

“…The TLR family member CD180, which regulates the phagocytosis of B . burgdorferi [15] was also present in the three fractions analyzed (Table 1). Analysis of the proteins identified showed the enrichment of components related to phagosome, endocytosis or antigen processing and presentation, particularly in fraction 6 and the pool of common proteins among the three fractions analyzed (Fig 1G).…”

“…We have recently described the regulation of macrophage surface receptors in response to the stimulation with B . burgdorferi that modulate both the capacity of these cells to phagocytose the spirochete and the ensuing inflammatory response [15]. B .…”

“…In contrast, CR3/CD14-mediated phagocytosis is independent of MyD88-induced signals and results in the downmodulation of the proinflammatory responses [14]. In fact, the repression of CR3 surface expression by the TLR family member, CD180, results in the effective modulation of both phagocytosis and proinflammatory responses [15]. Other signaling pathways have been described to be involved in the internalization of B .…”

“…In the case of B . burgdorferi , we have demonstrated that the response of macrophages to the spirochete is dependent on multiple signaling pathways [15] indicating that the array of receptors that trigger these responses is more complex than those already described.…”

“…burgdorferi . The analysis of the proteome of phagosome-enriched fractions containing the spirochete plus the use of multi-omic data previously generated [15] allowed us to define a set of receptors that modulate the uptake and/or proinflammatory cytokine production of macrophages in response to B . burgdorferi .…”