Research Article: Fine Tuning Inflammation at the Front Door: Macrophage Complement Receptor 3-mediates Phagocytosis and Immune Suppression for Francisella tularensis

Date Published: January 24, 2013

Publisher: Public Library of Science

Author(s): Shipan Dai, Murugesan V. S. Rajaram, Heather M. Curry, Rachel Leander, Larry S. Schlesinger, Denise M. Monack.


Complement receptor 3 (CR3, CD11b/CD18) is a major macrophage phagocytic receptor. The biochemical pathways through which CR3 regulates immunologic responses have not been fully characterized. Francisella tularensis is a remarkably infectious, facultative intracellular pathogen of macrophages that causes tularemia. Early evasion of the host immune response contributes to the virulence of F. tularensis and CR3 is an important receptor for its phagocytosis. Here we confirm that efficient attachment and uptake of the highly virulent Type A F. tularensis spp. tularensis strain Schu S4 by human monocyte-derived macrophages (hMDMs) requires complement C3 opsonization and CR3. However, despite a>40-fold increase in uptake following C3 opsonization, Schu S4 induces limited pro-inflammatory cytokine production compared with non-opsonized Schu S4 and the low virulent F. novicida. This suggests that engagement of CR3 by opsonized Schu S4 contributes specifically to the immune suppression during and shortly following phagocytosis which we demonstrate by CD11b siRNA knockdown in hMDMs. This immune suppression is concomitant with early inhibition of ERK1/2, p38 MAPK and NF-κB activation. Furthermore, TLR2 siRNA knockdown shows that pro-inflammatory cytokine production and MAPK activation in response to non-opsonized Schu S4 depends on TLR2 signaling providing evidence that CR3-TLR2 crosstalk mediates immune suppression for opsonized Schu S4. Deletion of the CD11b cytoplasmic tail reverses the CR3-mediated decrease in ERK and p38 activation during opsonized Schu-S4 infection. The CR3-mediated signaling pathway involved in this immune suppression includes Lyn kinase and Akt activation, and increased MKP-1, which limits TLR2-mediated pro-inflammatory responses. These data indicate that while the highly virulent F. tularensis uses CR3 for efficient uptake, optimal engagement of this receptor down-regulates TLR2-dependent pro-inflammatory responses by inhibiting MAPK activation through outside-in signaling. CR3-linked immune suppression is an important mechanism involved in the pathogenesis of F. tularensis infection.

Partial Text

Francisella tularensis is a remarkably infectious facultative intracellular pathogen that causes the zoonotic disease tularemia [1], [2]. F. tularensis can be divided into several subspecies, including tularensis, holarctica and mediasiatica[3], [4], with tularensis being the most virulent subspecies that can cause disease in humans through the respiratory route with <10 CFUs. F. novicida is normally considered to be the fourth subspecies of F. tularensis; however, recent genome-wide polymorphism analysis indicates that it is an independent species [5]. F. novicida rarely causes disease in humans but is virulent in mice, manifesting a disease that is similar to tularemia in humans, and has been widely used in the mouse model of tularemia. Because F. tularensis can be easily disseminated, results in a high mortality rate among untreated pulmonary cases, and has the potential to cause public panic, it is given the highest priority classification by the Centers for Disease Control and Prevention (CDC) as a Category A select agent and is a potential bioweapon [1]. F. tularensis is highly virulent with a very low dose of infection, which is often lethal before a fully effective adaptive immune response can be mounted [67], [68]. This high virulence and rapid lethality are at least partially due to the ability of F. tularensis to subvert or suppress host pro-inflammatory immune responses [16], [69]. F. tularensis infection of macrophages and dendritic cells leads to very limited secretion of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα [13]–[15], [70] and unresponsiveness to subsequent stimulation by TLR agonists [14], [15]. In the current study, we provide evidence for a pathway that links CR3-mediated phagocytosis for F. tularensis with immune suppression that involves crosstalk with TLR2.   Source:


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