A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

Abstract

Key Points• The natural inhibitor of neutrophil elastase, SLPI, is severely reduced in severe congenital neutropenia patients.• SLPI controls myeloid differentiation by regulation of NFkB, ERK1/2:LEF-1, and c-myc activation.We identified diminished levels of the natural inhibitor of neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), in myeloid cells and plasma of patients with severe congenital neutropenia (CN). We further found that downregulation of SLPI in CD34 1 bone marrow (BM) hematopoietic progenitors from healthy individuals resulted in markedly reduced in vitro myeloid differentiation accompanied by cell-cycle arrest and elevated apoptosis. Reciprocal regulation of SLPI by NE is well documented, and we previously demonstrated diminished NE levels in CN patients. Here, we found that transduction of myeloid cells with wild-type NE or treatment with exogenous NE increased SLPI messenger RNA and protein levels, whereas transduction of mutant forms of NE or inhibition of NE resulted in downregulation of SLPI. An analysis of the mechanisms underlying the diminished myeloid differentiation caused by reduced SLPI levels revealed that downregulation of SLPI with short hairpin RNA (shRNA) upregulated nuclear factor kB levels and reduced phospho-extracellular signal-regulated kinase (ERK1/2)-mediated phosphorylation and activation of the transcription factor lymphoid enhancer-binding factor-1 (LEF-1). Notably, microarray analyses revealed severe defects in signaling cascades regulating the cell cycle, including c-Myc-downstream signaling, in myeloid cells transduced with SLPI shRNA. Taken together, these results indicate that SLPI controls the proliferation, differentiation, and cell cycle of myeloid cells. (Blood. 2014;123(8):1239-1249

Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop

“…In total, 748 genes were significantly upregulated, while 1149 genes were downregulated (p < 0.05, fdr < 0.28). Myeloid-specific genes and quiescence regulators were expressed at higher levels (Figure 1G) (Table S1) (Ardi et al, 2007; Klimenkova et al, 2014; Land et al, 2015; Schinke et al, 2015), whereas lymphoid-specific, cell cycle, DNA replication, and mitochondrial function genes were downregulated in Hdc-GFP hi HSCs (Figure 1H-J and S2P) (Table S1) (Cheung and Rando, 2013; Guo et al, 2009; Jung et al, 2006; Siggs et al, 2011; Viatour et al, 2008). These results are consistent with the observed myeloid bias and quiescence of Hdc-GFP hi HSCs.…”

Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

“…Thus, one cannot exclude that FS areas were already present in other areas of the primary lesions. Interestingly, however, these patients without an apparent FS component at onset had the longest previous relapse-free survival (25,22, and 10 years). Thus, retrospective studies on surgical series with an updated pathologic review are needed to clarify to which extent classic DFSP, i.e., those without any FS aspect, do have a metastatic potential.…”

“…In all cases, the pathologic appearance was consistent with an FS-DFSP. The primary tumor showed classic DFSP aspects without an FS component in 3 patients, who had the longest relapse-free survival (25,22, and 10 years). In 6 cases, the primary tumor retained focal marginal areas of classic/ low-grade DFSP together with FS areas featuring spindle cells; one case showed myxoid aspects.…”

Uniquely altered transcripts are associated with immune preservation in HIV infection

“…It is interesting to note that one of the natural regulators of neutrophil elastase, the secretory leukocyte protease inhibitor (SLPI) [40, 41], was also found to be consistently upregulated only in the same immune responders before cART, confirming its well-documented dose-dependent reciprocal feedback regulation [42–44]. In addition to its antiprotease activity, SLPI has been shown to inhibit NF-kB activation in monocytes [45], exerting anti-inflammatory effects, and to inhibit the ELA2-dependent conversion of proepithelin to epithelin, thereby stimulating wound healing by promoting epithelial cell growth [46].…”