HDAC Inhibitors as Epigenetic Regulators

Ingestion and intracellular survival of in human and bovine polymorphonuclear leukocytes. in PMNd-mice. These results demonstrate that PMNs have an active role in modulating the course of infection after the adaptive immune response has already developed. infection (4, 15). organisms are intracellular stealth pathogens of animals and humans that avoid the activation of innate immunity, remaining in several tissues for protracted periods (15,C17). readily invades PMNs, resisting the killing action of these leukocytes (15, 18,C22). This correlates with the resistance and modification of the bacterial cell envelope components, which barely promote the generation of reactive oxygen species and proinflammatory cytokines in the infected PMNs (15, 19). In addition, through its lipopolysaccharide (mediates in a nonphlogistic manner the premature cell death of PMNs and induces the expression of NGFR eat me signals on these cells (19, 21). The absence of PMNs at the onset of infection stimulates the recruitment of monocytes/dendritic cells, favors the activation of B and T lymphocytes, and promotes the production of Th1 cytokines (4). The course of human brucellosis parallels that observed in mice (16, 23). In the mouse model, brucellosis is divided into four phases according to the bacterial colonization of the target organs, the pathological signs, and the profile of the immune response (17, 23). The first phase corresponds to the onset of infection (also known as the incubation stage), which typically lasts 2 to 3 3?days. During this phase, the production of proinflammatory cytokines and the activation of innate immunity are negligible (4). The acute phase follows, lasting 2 to 3 3?weeks. Active bacterial replication Boc-NH-C6-amido-C4-acid and high Boc-NH-C6-amido-C4-acid levels of Th1 cytokines characterize this phase (23, 24). Then, the chronic steady phase, lasting from 8 Boc-NH-C6-amido-C4-acid to 11?weeks, corresponds to the plateau of the infection. Finally, the chronic declining phase is characterized by the gradual elimination of bacteria. This phase may last months or even years (23, 24). During the acute and chronic phases, large amounts of anti-organisms, maintaining for protracted periods high bacterial loads within BM PMNs and, to a minor extent, in monocytes and stem cells (17). This is significant, since PMNs in other target organs, such as the spleen, do not harbor (26). Here, we describe how PMNs modulate adaptive immunity in the initial stages of acute murine brucellosis. The results presented here reinforce our previous hypothesis (4) and give new insights into the role that PMNs have in shaping the immune response during brucellosis. RESULTS The absence of PMNs enhances the removal of in mice. We have shown that the absence of PMNs at the onset of infection enhances bacterial removal after several days (4). Following this, we explored whether the absence of PMNs has any influence at the onset of adaptive immunity, once Boc-NH-C6-amido-C4-acid Th1 cytokines and specific antibodies have developed (21). For this, the protocols described in Fig. S1A and B in the supplemental material were followed. After the sixth day of infection (1 day after PMN depletion), we observed Boc-NH-C6-amido-C4-acid an initial increase of bacterial loads in the spleens of PMNd-mice (Fig. 1A). This outcome agreed with our previous results (4). After 14?days of infection (9 days post-PMN depletion), the numbers of CFU in the spleens of PMNd-mice reached values similar to those of the non-PMN-depleted controls (Fig. 1A); however, PMNd-mice showed more efficient bacterial removal (Fig. 1B). This phenomenon was more conspicuous after 30?days of infection (15?days of PMN depletion) (Fig. 2). Open in a separate windowpane FIG 1 PMN depletion in the onset of adaptive immunity promotes removal. C57BL/6 mice were i.p. infected with 0.1?ml of PBS containing 106 CFU of 2308W. After 5?days of illness, one group of mice was depleted of PMNs by means of i.p. injection of RB6-8C5 anti-PMN. (A) In the indicated instances, the numbers of CFU per spleen and spleen weights were identified. Each sign represents one animal, and the lines represent the medians for each group. p. d, postdepletion. (B) Rates of switch in CFU per spleen ( CFU/spleen) and CFU per spleen excess weight ( CFU/g of spleen) were calculated over time using the following equations: CFU/spleen = mean CFU 14?days/CFU 6?day standard deviation (SD) and CFU/g of spleen = imply CFU/g of spleen 14?days/6?days SD. The error bars represent standard deviations. *, removal..