No abstract

Signal transducer and activator of transcription 4 (STAT4) is expressed in hematopoietic cells and plays a key role in the differentiation of T helper 1 cells. Although STAT4 is required for immunity to intracellular pathogens, the T cell-independent protective mechanisms of STAT4 are not clearly defined. In this report, we demonstrate that STAT4-deficient mice are acutely sensitive to methicillin-resistant Staphylococcus aureus (MRSA) infection. We show that STAT4 is expressed in neutrophils and activated by IL-12 via a Jak2-dependent pathway. We demonstrate that STAT4 is required for multiple neutrophil functions including IL-12-induced ROS production, chemotaxis, and production of the neutrophil extracellular traps.Importantly, myeloid-specific and neutrophil-specific deletion of STAT4 results in enhanced susceptibility to MRSA, demonstrating the key role of STAT4 in the in vivo function of these cells. Thus, these studies identify STAT4 as an essential regulator of neutrophil functions and a component of innate immune responses in vivo.

Myeloid cells are critical for systemic inflammation, microbial control, and organ damage during sepsis. MicroRNAs are small noncoding RNAs that can dictate the outcome of sepsis. The role of myeloid-based expression of microRNA-21 (miR-21) in sepsis is inconclusive. In this study, we show that sepsis enhanced miR-21 expression in both peritoneal macrophages and neutrophils from septic C57BL/6J mice, and the deletion of miR-21 locus in myeloid cells (miR-21Δmyel mice) enhanced animal survival, decreased bacterial growth, decreased systemic inflammation, and decreased organ damage. Resistance to sepsis was associated with a reduction of aerobic glycolysis and increased levels of the anti-inflammatory mediators PGE2 and IL-10 in miR-21Δmyel in vivo and in vitro. Using blocking Abs and pharmacological tools, we discovered that increased survival and decreased systemic inflammation in septic miR-21Δmyel mice is dependent on PGE2/IL-10–mediated inhibition of glycolysis. Together, these findings demonstrate that expression of miR-21 in myeloid cells orchestrates the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm during sepsis.

Melo, P.H. The role of TNF receptors in the development of sepsis-induced immunossupression. 2013. 149 f. Dissertation (Mestrado)

Myeloid cells play a critical role in the development of systemic inflammation and organ damage during sepsis. The mechanisms the development of aberrant inflammatory response remains to be elucidated. MicroRNAs are small non-coding RNAs that could prevent the expression of inflammatory molecules. Although the microRNA-21 (miR-21) is abundantly expressed in macrophages, the role of miR-21 in sepsis is controversial. Here we showed that miR-21 is upregulated in neutrophils and macrophages from septic mice. We found that myeloid-specific miR-21 deletion enhances animal survival, followed by decreased bacterial growth and organ damage during sepsis. Increased resistance against sepsis was associated with a reduction of aerobic glycolysis (as determined by reduced extracellular acidification rate (ECAR) and expression of glycolytic enzymes) and systemic inflammatory response (IL-1TNF and IL-6).While miR-21-/-macrophages failed to induce aerobic glycolysis and production of proinflammatory cytokines, we observed increased levels of the anti-inflammatory mediators' prostaglandin E2 (PGE2) and IL10. Using blocking antibodies and pharmacological tools, we further discovered that increased survival and decreased systemic inflammation in miR21myel during sepsis is dependent on the PGE2/IL10-mediated glycolysis inhibition. Together, we are showing a heretofore unknown role of macrophage miR21 in the orchestrating the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm and tissue damage during sepsis. expression of glycolytic enzymes and transports leads to aerobic glycolysis in macrophages (21,22). Aerobic glycolysis is a critical metabolic pathway required for macrophage activation and proinflammatory activity (23-25). The blockage of glycolysis in macrophages showed a crucial role in the reduction of systemic inflammation leads to improvement of sepsis outcome in experimental models (10,21,26). Exaggerated production of inflammatory mediators and aerobic glycolysis are critical determinants of organ dysfunction during sepsis (27,28).Recent studies have shown that miRNA expression is associated with severe illness and suggested it as potential mediators during sepsis (29). microRNA (miRNAs) are small non-coding RNA molecules (18-to 23-nucleotides) that regulate gene expression by translational repression or posttranscriptional suppression (30,31). miRNAs have an essential role in several biological processes, such as development, differentiation, cell survival, and inflammatory response (32). miRNAs regulate phagocyte cytokine and chemokine response, antimicrobial effector function, pathogen recognition, and tissue repair. The microRNA-21 (miR-21) is highly expressed in different immune cells, such as T/B lymphocytes, monocytes, macrophages, and dendritic cells (33). In vitro studies showed that several inflammatory stimuli as LPS and cytokines as IL-6, TFGβ, and TNF- induce miR21 expression (34,35). Our laboratory showed that miR21 deficiency accounted for the homeostatic...