Sepsis inflammation accelerates myeloid cell generation to compensate for rapid mobilization of the myeloid progenitors from bone marrow. This inflammation-driven myelopoiesis, however, generates myeloid progenitors with immunosuppressive functions that are unable to differentiate into mature, innate immune cells. The myeloid-derived suppressor cells (MDSCs) expand markedly in the later phases of sepsis, suppress both innate and adaptive immunity, and thus, elevate mortality. Using a murine model with myeloid-restricted deletion of the C/EBPβ transcription factor, we show that sepsis-induced generation of MDSCs depends on C/EBPβ. C/EBPβ myeloid cell-deficient mice did not generate MDSCs or develop immunosuppression and survived sepsis. However, septic mice still generated Gr1CD11b myeloid progenitors at the steady-state levels similar to the control sham mice, suggesting that C/EBPβ is not involved in healthy, steady-state myelopoiesis. C/EBPβ-deficient Gr1CD11b cells generated fewer monocyte- and granulocyte-like colonies than control mice did, indicating reduced proliferation potential, but differentiated normally in response to growth factors. Adoptive transfer of C/EBPβ-deficient Gr1CD11b cells from late septic mice exacerbated inflammation in control mice undergoing early sepsis, confirming they were not immunosuppressive. These results show that C/EBPβ directs a switch from proinflammatory to repressor myeloid cells and identifies a novel treatment target.

Myeloid progenitor-derived suppressor cells (MDSCs) arise from myeloid progenitors and suppress both innate and adaptive immunity. MDSCs expand during the later phases of sepsis in mice, promote immunosuppression, and reduce survival. Here, we report that the myeloid differentiation-related transcription factor nuclear factor I-A (NFI-A) controls MDSC expansion during sepsis and impacts survival. Unlike MDSCs, myeloid cells with conditional deletion of the Nfia gene normally differentiated into effector cells during sepsis, cleared infecting bacteria, and did not express immunosuppressive mediators. In contrast, ectopic expression of NFI-A in myeloid progenitors from NFI-A myeloid cell-deficient mice impeded myeloid cell maturation and promoted immune repressor function. Importantly, surviving septic mice with conditionally deficient NFI-A myeloid cells were able to respond to challenge with bacterial endotoxin by mounting an acute inflammatory response. Together, these results support the concept of NFI-A as a master molecular transcriptome switch that controls myeloid cell differentiation and maturation and that malfunction of this switch during sepsis promotes MDSC expansion that adversely impacts sepsis outcome.KEYWORDS inflammation, sepsis immunosuppression, MDSCs, NFI-A, sepsis M yeloid progenitor-derived suppressor cells (MDSCs) represent a heterogenous population of immature myeloid cells that includes progenitors and precursors of monocytes/macrophages, granulocytes, and dendritic cells (1-3). MDSCs are generated under a variety of inflammatory and infection conditions (1, 2) and are best characterized by their immunosuppressive functions (4-6). They may also promote persistent inflammation and chronic infection with catabolism during chronic sepsis (7). MDSCs suppress both innate and adaptive immunity via production of immunosuppressive mediators and inhibition of T cell proliferation and activation (3,4,8). Phenotypically, murine MDSCs coexpress the myeloid differentiation markers Gr1 and CD11b, similarly to the Gr1 ϩ CD11b ϩ myeloid progenitors that arise under normal physiological conditions (2, 9). Unlike the immunosuppressive Gr1 ϩ CD11b ϩ cells (i.e., MDSCs), normal Gr1 ϩ CD11b ϩ cells can differentiate into competent innate immune cells (3). Elimination of MDSCs in tumor-bearing mice enhances antitumor immunity (10). Since MDSCs are "immature" cells that deviate from the standard path of differentiation, it has been suggested that arrested myeloid cell differentiation and maturation may be responsible for MDSC generation and immunorepression (2, 6). How immature myeloid cells lose their ability to differentiate and instead generate MDSCs remains unclear. Some studies, however, have suggested that MDSCs retain their potential to differentiate and mature but are trapped in a MDSC phenotype in the environmental milieu of chronic inflammation or growing tumors (1). In support of this, Kusmartsev et al. (10) reported that MDSCs from tumor-bearing mice could differentiate into macrophages and...

Sepsis-induced immunosuppression increases the risk of chronic infection and reduces survival. Myeloid-derived suppressor cells (MDSCs) expand in the bone marrow and spleen during murine polymicrobial sepsis, contributing to immunosuppression. A better understanding of molecular controls of MDSC production is needed to identify treatment targets. We previously reported that miR-21 and miR-181b couple with transcription factor NFI-A to induce MDSCs during murine sepsis. Here, we expand upon these observations by showing that conditional deletion of the Nfia gene in the myeloid lineage precludes MDSC development. NFI-A-deficient Gr1CD11b myeloid cells are not immunosuppressive and differentiate normally into macrophages and dendritic cells. In contrast, ectopically expressed NFI-A prevents differentiation of these immature Gr1CD11b cells, while converting them into MDSCs. In addition, NFI-A-deficient Gr1CD11b cells decreased, and cells transfected with NFI-A increase expression of miR-21 and miR181b. Our results support a myeloid cell loop in which NFI-A and miR-21 and miR-181b sustain Gr1CD11b MDSC-dependent immunosuppression during sepsis.

Pseudomonas aeruginosa is an important pathogen of the immunocompromised, causing both acute and chronic infections. In cystic fibrosis (CF) patients, P. aeruginosa causes chronic disease. The impressive sensory network of P. aeruginosa allows the bacterium to sense and respond to a variety of stimuli found in diverse environments. Transcriptional regulators, including alternative sigma factors and response regulators, integrate signals changing gene expression, allowing P. aeruginosa to cause infection. The two-component transcriptional regulator AlgR is important in P. aeruginosa pathogenesis in both acute and chronic infections. In chronic infections, AlgR and the alternative sigma factor AlgU activate the genes responsible for alginate production. Previous work demonstrated that AlgU controls rsmA expression. RsmA is a posttranscriptional regulator that is antagonized by two small RNAs, RsmY and RsmZ. In this work, we demonstrate that AlgR directly activates rsmA expression from the same promoter as AlgU. In addition, phosphorylation was not necessary for AlgR activation of rsmA using algR and algZ mutant strains. AlgU and AlgR appear to affect the antagonizing small RNAs rsmY and rsmZ indirectly. RsmA was active in a mucA22 mutant strain using leader fusions of two RsmA targets, tssA1 and hcnA. AlgU and AlgR were necessary for posttranscriptional regulation of tssA1 and hcnA. Altogether, our work demonstrates that the alginate regulators AlgU and AlgR are important in the control of the RsmA posttranscriptional regulatory system. These findings suggest that RsmA plays an unknown role in mucoid strains due to AlgU and AlgR activities.IMPORTANCE P. aeruginosa infections are difficult to treat and frequently cause significant mortality in CF patients. Understanding the mechanisms of persistence is important. Our work has demonstrated that the alginate regulatory system also significantly impacts the posttranscriptional regulator system RsmA/Y/Z. We demonstrate that AlgR directly activates rsmA expression, and this impacts the RsmA regulon. This leads to the possibility that the RsmA/Y/Z system plays a role in helping P. aeruginosa persist during chronic infection. In addition, this furthers our understanding of the reach of the alginate regulators AlgU and AlgR.KEYWORDS P. aeruginosa, RsmA, AlgR, mucoid, Pseudomonas aeruginosa, cystic fibrosis, mucA, two-component regulatory systems T he opportunistic pathogen Pseudomonas aeruginosa possesses multiple virulence factors for causing disease. This allows P. aeruginosa to cause both acute and chronic infections. Acute infecting strains are characterized by the presence of type IV pili (T4P), flagella, and a type III secretion system (T3SS) (1-3). In contrast, chronic infecting strains diversify (4, 5) and frequently do not express T3SS, T4P, or flagella (6, 7). Chronic infecting strains often form biofilms composed of exopolysaccharides, such as alginate, and signal a decline in lung function in CF patients (8-11). Alginate

This study evaluated the relationship between pain self-efficacy, occupational performance, and satisfaction with performance in clients with chronic pain who participated in a hospital-based pain management program. Self-efficacy was measured using the Pain Self-Efficacy Questionnaire (Nicholas, 1988). Occupational performance and satisfaction were measured using the Canadian Occupational Performance Measure (Law et al., 1998). Data were collected from 64 clients who completed both measures before and after a 3-week pain management program. Results of the study demonstrated a positive difference between pain self-efficacy and occupational performance (t = 4.43, df = 62, p < .05), and between pain self-efficacy and satisfaction (t = 4.02, df = 62, p < .05). This research suggests that therapy should address the beliefs of clients about their abilities to perform occupations when living with chronic pain (Strong, 1995) and reinforces the use of the Pain Self-Efficacy Questionnaire and Canadian Occupational Performance Measure as reliable and valid assessment measures for those with chronic pain.

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