Induction of a Potential Paracrine Angiogenic Loop between Human THP-1 Macrophages and Human Microvascular Endothelial Cells duringBartonella henselaeInfection

Abstract

Bartonella henselae is responsible for various disease syndromes that loosely correlate with the immune status of the host. In the immunocompromised individual, B. henselae-induced angiogenesis, or bacillary angiomatosis, is characterized by vascular proliferative lesions similar to those in Kaposi's sarcoma. We hypothesize that B. henselae-mediated interaction with immune cells, namely, macrophages, induces potential angiogenic growth factors and cytokines which contribute in a paracrine manner to the proliferation of endothelial cells. Vascular endothelial growth factor (VEGF), a direct inducer of angiogenesis, and interleukin-1␤ (IL-1␤), a potentiator of VEGF, were detected within 12 and 6 h, respectively, in supernatants from phorbol 12-myristate 13-acetate-differentiated human THP-1 macrophages exposed to live B. henselae. Pretreatment of macrophages with cytochalasin D, a phagocytosis inhibitor, yielded comparable results, suggesting that bacterium-cell attachment is sufficient for VEGF and IL-1␤ induction. IL-8, an angiogenic cytokine with chemotactic properties, was induced in human microvascular endothelial cells (HMEC-1) within 6 h of infection, whereas no IL-8 induction was observed in infected THP-1 cells. In addition, conditioned medium from infected macrophages induced the proliferation of HMEC-1, thus demonstrating angiogenic potential. These data suggest that Bartonella modulation of host or target cell cytokines and growth factors, rather than a direct role of the bacterium as an endothelial cell mitogen, is the predominant mechanism responsible for angiogenesis. B. henselae induction of VEGF, IL-1␤, and IL-8 outlines a broader potential paracrine angiogenic loop whereby macrophages play the predominant role as the effector cell and endothelial cells are the final target cell, resulting in their proliferation.

The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae

“…Colonization of endothelial cells is important in both reservoir and incidental mammalian hosts and is considered essential for the establishment and maintenance of the angioproliferative lesions (4,(6)(7)(8).…”

Structure and Biological Activity of the Short-chain Lipopolysaccharide from Bartonella henselae ATCC 49882T

“…henselae is considered to provoke angioproliferation by at least two independent mechanisms (4): directly, by triggering proliferation (5) and inhibiting apoptosis of endothelial cells (6) and indirectly, by stimulating a paracrine angiogenic loop of vascular endothelial growth factor production by infected macrophages (7).…”

Infections and cardiovascular disease: is Bartonella henselae contributing to this matter?

“…T r a n s p la n t a t io n Resto-Ruiz et al, 2002), recruited to the site of infection as a result of proinflammatory response in ECs (Fuhrmann et al, 2001;Schmid et al, 2004) or from infected epithelial cells surrounding the blood vessels (Kempf et al, 2001). This mechanism has been proposed to contribute to BA (cutaneous manifestations) or BP (hepatic manifestations) by promoting EC proliferation in a paracrine manner (Deng et al, 2012;Harms & Dehio, 2012).…”

“…Mechanisms required to infect human erythrocytes and ECs are (i) massive rearrangements of actin cytoskeleton with formation of bacterial aggregates (invasome) (Dehio, 2001); (ii) NFkB-dependent proinflammatory activation, leading to adhesion molecule expression and chemokine secretion (Kempf et al, 2001;Resto-Ruiz et al, 2002); (iii) inhibition of apoptosis (Kirby & Nekorchuk, 2002); (iv) two T4SSs (Trw and VirB) to adapt to a wide range of mammalian hosts, both essential for the interaction with the host but at different stages of the infection cycle (Okujava et al, 2014).…”