Myeloid Cell-Specific Knockout of NFI-A Improves Sepsis Survival

Abstract

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...

Neutrophil Diversity in Health and Disease

“…Moreover, retro-transmigrated neutrophils express CD54 and have been associated with secondary organ damage [14], as well as with effective bacterial phagocytosis during sepsis [95] (Figure 2). Overall, although the specific neutrophil subpopulations found in mouse models do not completely mirror their human counterparts (i.e., from cell-surface markers), important similarities are shared in terms of functionality (i.e., immunosuppressive activity, APC functions), as well as their influence on the outcomes of infections [84,[86][87][88]93,94]. As a result, mouse models are invaluable in that they can shed light on the importance of specific pathogen infections as possible sources of neutrophil heterogeneity; this information might in turn help in the development of tailored therapeutic strategies to improve host immune defense.…”

“…In addition, populations of mature activated suppressive neutrophils can be present in both the LDN and NDN fractions [63,72], or can be obtained by red blood cell lysis without performing density gradient centrifugation [73]. Mice: as observed in humans, pathogen infections of different types may induce the appearance of immature PMN-MDSCs with immunosuppressive functions in the circulation (LDNs/PMN-MDSCs) and infected tissues (PMN-MDSCs) [85][86][87][88]94]. In Staphylococcus aureus or Candida albicans models of infection, two subpopulations of neutrophils with opposite functions (proinflammatory, CD11b − CD49d + IL-12 + ; anti-inflammatory, CD11b + CD49d − IL-10 + ) have been identified [84].…”

“…As extensively reviewed elsewhere, pioneering papers have shown that different subpopulations of neutrophils develop (proinflammatory, CD11b − CD49d + IL-12 + ; anti-inflammatory, CD11b + CD49d − IL-10 + ), as in the case of methicillin-resistant S. aureus infections [14,84] (Figure 1). Recently, in mouse models of acute infection with Japanese encephalitis virus [85], chronic infection with Myobacterium tuberculosis [86], or in polymicrobial sepsis [87], populations of PMN-MDSCs were shown to inhibit CD4 + T cell proliferation and IFN-γ production, and also reduced differentiation and IL-21 production of T follicular helper cells, that in turn support pathogen immune evasion ( Figure 2). Moreover, pathogen dose can also be decisive during host defense, inducing neutrophils harboring opposite functions.…”

Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections

“…These requirements resemble those observed for MDSC in cancer ( 63 ). In sepsis, myeloid specific deletion of the myeloid differentiation-related transcription factor nuclear factor I-A, or deletion of the transcription factor C/EBPβ, result in reduction of MDSC, including M-MDSC ( 76 , 77 ). Pro-inflammatory cytokines, notably IL-6, TNF-α, and IL-1, drive generation of MDSC in various infection models.…”

“…E.g., M-MDSC are host-protective in certain fulminant acute infections by restricting immunopathology ( 35 , 112 , 159 ). During late sepsis, the immature total MDSC population aggravates disease ( 76 , 77 , 160 ). M-MDSC may, however, be harmful in acute infection with intracellular microbes, notably francisellae ( 42 ).…”