Impact of Neutrophil-Secreted Myeloid Related Proteins 8 and 14 (MRP 8/14) on Leishmaniasis Progression

Abstract

The myeloid-related proteins (MRPs) 8/14 are small proteins mainly produced by neutrophils, which have been reported to induce NO production in macrophages. On the other hand, Leishmania survives and multiplies within phagocytes by inactivating several of their microbicidal functions. Whereas MRPs are rapidly released during the innate immune response, their role in the regulation of Leishmaniasis is still unknown. In vitro experiments revealed that Leishmania infection alters MRP-induced signaling, leading to inhibition of macrophage functions (NO, TNF-α). In contrast, MRP-primed cells showed normal signaling activation and NO production in response to Leishmania infection. Using a murine air-pouch model, we observed that infection with L. major induced leukocyte recruitment and MRP secretion comparable to LPS-treated mice. Depletion of MRPs significantly reduced these inflammatory events and augmented both parasite load and footpad swelling during the first 8 weeks post-infection, as also observed in MRP KO mice. On the contrary, mouse treatment with recombinant MRPs (rMRPs) had the opposite effect. Collectively, our results suggest that rapid secretion of MRPs by neutrophils at the site of infection may protect uninfected macrophages and favor a more efficient innate inflammatory response against Leishmania infection. In summary, our study reveals the critical role played by MRPs in the regulation of Leishmania infection and how this pathogen can subvert its action.

Calprotectin induces cell death in human prostate cancer cell (LNCaP) through survivin protein alteration

“…As shown in Figure , concentrations over 100 µg/mL after 24 h had significant cytotoxic impact on cell viability. Cell growth inhibitory effect of CP against various cells ranging from normal fibroblast cells to several tumor cells has been demonstrated by different research groups (Contreras et al, ; Yui et al, ; Zali et al, ). Following this observation we performed other experiments to elucidate the possible mechanism(s) by which CP mediates LNCaP cell viability inhibition.…”

Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis

“…Mrp8 and Mrp14 (calprotectin) have been identified as biomarkers of the aging process [3], but while their pro-inflammatory activity has been documented in young mice under acute stress [16–23], their contributions to chronic inflammation at older ages remains unclear. This study compared Mrp14-KO and WT mice at young and old ages but obtained no evidence that age-related inflammation is blunted by Mrp8/Mrp14 deficiency.…”

“…Most studies have identified Mrp14-KO phenotypes only in the context of acute pro-inflammatory stimuli [16–23], which has fostered the view that KO and WT mice differ little under standard physiological conditions [16, 17]. This conflicts with our observations, however, since we identified 215 genes differentially expressed between livers from KO and WT mice at 5 months of age, in the absence of any stressful or pro-inflammatory conditions (Figures 2 and 3).…”

“…Nearly all functional studies of calprotectin have been performed using young mice [16–23]. The contributions of Mrp8 and Mrp14 to age-related pathology have therefore remained uncertain.…”

“…Under normal physiological conditions, studies of young Mrp14 (−/−) mice have frequently failed to identify phenotypes that differ significantly from wild-type controls [16, 17]. Phenotypic differences have emerged, however, following stressful or pro-inflammatory stimuli, such as E. coli -induced sepsis [18], intraperitoneal LPS administration [6], carbon tetrachloride (CCl 4 ) toxicity [19], lung injury [20], and infection [21–23]. In general, inflammatory responses to these treatments are diminished in Mrp14 (−/−) mice as compared to wild-type controls.…”